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Multiple Sclerosis and the Blood-Central Nervous System Barrier

Multiple Sclerosis and the Blood-Central Nervous System Barrier HindawiPublishingCorporation CardiovascularPsychiatryandNeurology Volume2013,ArticleID530356,10pages http://dx.doi.org/10.1155/2013/530356 ReviewArticle AlanM.Palmer MSerapeuticsLtd.,BeecheyHouse,87ChurchStreet,Crowthorne,BerksRG457AW,UK CorrespondenceshouldbeaddressedtoAlanM.Palmer;alan.palmer@mstherapeutics.com Received22October2012;Revised25December2012;Accepted25December2012 AcademicEditor:GjumrakchAliev Copyright©2013AlanM.Palmer. is is an open access article distributed under the Creative Commons Attribution License, whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. e central nervous system (CNS) is isolated from the blood system by a physical barrier that contains efflux transporters and catabolicenzymes.isblood-CNSbarrier(BCNSB)playsapivotalroleinthepathophysiologyofmultiplesclerosis(MS).Itbinds andanchorsactivatedleukocytestopermittheirmovementacrosstheBCNSBandintotheCNS.Oncethere,theseimmunecells target particular self-epitopes and initiate a cascade of neuroin�ammation, which leads to the breakdown of the BCNSB and the formation of perivascular plaques, one of the hallmarks of MS. Immunomodulatory drugs for MS are either biologics or small molecules, with only the latter having the capacity to cross the BCNSB and thus have a propensity to cause CNS side effects. However,BCNSBpenetrationisadesirablefeatureofMSdrugsthathavemoleculartargetswithintheCNS.esearenabiximols and dalfampridine, which target cannabinoid receptors and potassium channels, respectively. Vascular cell adhesion molecule-1, presentonendothelialcellsoftheBCNSB,alsoservesasadrugdiscoverytargetsinceitinteractswith𝛼𝛼4-𝛽𝛽1-integrinonleucocytes. eMSdrugnatalizumab,ahumanizedmonoclonalantibodyagainst𝛼𝛼4-𝛽𝛽1-integrin,blocksthisinteractionandthusreducesthe movement of immune cells into the CNS. is paper further elaborates on the role of the BCNSB in the pathophysiology and pharmacotherapyofMS. but with insu�cient evidence for a de�nitive diagnosis of 1.Introduction MS[9,10].isisreferredtoasclinicallyisolatedsyndrome Multiple sclerosis (MS) is an acquired autoimmune disease and, in most cases (80% aer 20 years), progresses to RRMS that affects both the brain and the spinal cord leading to a [11]. At the other end of the RRMS continuum is secondary variety of symptoms, including changes in motor function, progressive MS (SPMS). e majority of those with RRMS senseperception,andmentalfunction,alongwithfatigue[1– converttoSPMSwithintwoorthreedecades.Ithasasimilar 3].ediseasepresentsindifferentformsthatfollowdistinct progressive and irreversible course to that of PPMS [12– patterns of evolution and rates of disability progression [4]. 14]. A �nal subset, which resembles RRMS, is progressive e most common form is relapsing-remitting MS (RRMS), relapsing MS, which affects less than 5% of pwMS. It is whichaffectsabout85%ofpeoplewithMS(pwMS),ismore characterizedbyasteadydeclineinneurologicfunctionand common in females than males (by a ratio of 2 to 1), and clearsuperimposedexacerbations[4]. has an average age at diagnosis of 29 years [5]. RRMS is MRIplaysanincreasinglyimportantroleinthediagnosis characterized by acute attacks (relapses) followed by partial andmanagementofMS. Itisalso routinelyused asthepri- or full recovery (remission) and contrasts with primary mary endpoint in proof-of-concept clinical trials evaluating progressive MS (PPMS), which affects about 10–15% of potentialnewdrugsforMS,andasthesecondaryendpointin pwMS,isdiagnosed(onaverage)atage40,hasnogenderbias, de�nitivephaseIIItrials[15].MRIscansdistinguishfatfrom and is characterized by a steady and irreversible progression water.InT -weightedimageswaterisdarkerandfatbrighter, offunctionalimpairments[6–8].esetwoformsofMSalso whereastheoppositeisthecase in T -weighted scans. Since differ in their onset as PPMS begins insidiously, whereas myelinispredominantlylipid(andthushydrophobic),areas the harbinger of RRMS is usually a transient impairment ofdemyelinationholdmorewaterandsoshowupaseithera in motor or sensory function, together with white matter brightwhitespot(inaT -weightedscan)oradarkenedarea abnormalitiesshownbymagneticresonanceimaging(MRI), (in a T -weighted scan). e sensitivity of the T -weighted 1 1 2 CardiovascularPsychiatryandNeurology scansisoenenhancedbytheuseofcontrastagents,suchas the arachnoid villi. Both the BBB and the BSCB comprise gadoliniumdiethylenetriaminepentaaceticacid.Gadolinium theendothelialcellsofCNSbloodvessels,alongwithathick enhancement permits direct visualization of breaches in basement membrane and astrocytes. ey display a unique the BCNSB that accompany acute MS and so is used to phenotype characterized by the presence of endothelial cells visualize the number of new plaques in the CNS (usually thatareconnectedbyanintercellularadhesioncomplex.is the brain) of pwMS. It therefore provides a good measure forms the close contact between the adjacent cells known as of disease activity and helps distinguish between acute (or tightjunctions.isbarrierfunctionoftheBCNSBisfurther active)plaquesandchronic(ornonactive)lesions[16].Inthe enhancedbytherelativepaucityoffenestraeandpinocytotic brain,MSplaquesarecommonlyroundorovoidandrangein vesicles.Collectively,thisresultsinalowlevelofendocytosis sizefromafewmmtomorethan1cmandareoenfoundin and transcytosis, which severely restricts the movement of the brainstem, cerebellum, and periventricular white matter molecules and cells into the CNS via the transcellular route [17–19]. [34]. Plaques are regions of demyelination and neuronal loss. e BCNSB has two further barrier elements: (i) a ey occur as a consequence of the movement of activated metabolic barrier that contains a complex array of enzymes immune cells from the bloodstream into the brain or spinal (including acetylcholinesterase, alkaline phosphatase, 𝛾𝛾 - cord (or both) across the blood-CNS barrier (BCNSB) [20]. glutamyl transpeptidase, and monoamine oxidases) that e cascade of in�ammatory change is probably initiated by degrade different chemical compounds thus altering their + + autoreactive T-cells, particularly CD4 and CD8 T helper pharmacologicalactivityand(ii)atransportbarrierthatcon- ()cells.CD4 cellsrecognizeantigensthatarepresentedby tainsavarietyofeffluxtransporters,includingP-glycoprotein majorhistocompatibilitycomplex(MHC)moleculesonspe- andbreastcancerresistanceprotein[34,37,38]. cializedantigen-presentingcellsandpresentthemtospeci�c TightjunctionsarethecriticalcomponentoftheBCNSB T cell receptors [21]. e activation of immune cells by an astheycontrolparacellulardiffusionandmaintainthestruc- tural and functional polarity of the specialized endothelial autoantigen leads the CD4 cells to commence pathological destruction of cells of self, particularly myelinated CNS cells of the BBB and BSCB. us, the BCNSB contributes to neurons. e most prominent candidates for autoantigens thehomeostasisof theparenchymaofthebrainandspinal are proteins present in myelin, such as myelin basic protein, cordandprovidesprotectionagainstmanytoxiccompounds myelinoligodendroglialglycoprotein,neurofascinandprote- and pathogens [34, 36, 39]. Indeed, the BCNSB is largely olipid protein. Other candidates include stress proteins such impermeabletocompoundsthatarenotlipophilicandhavea as B crystallin, which is found in the myelin sheath aer molecularweightgreaterthan450Da.ispresentsamajor activationviathein�ammatoryresponse[22,23]. challengeforCNSdrugdiscovery[40,41]. ecause ofMS isnotyetunderstood, butitisknown thatdozensofgeneticvariationsactinconcertwithenviron- 3.TheRoleoftheImmuneSysteminMS mentalfactorstotriggerdiseasepathogenesis.Evidenceindi- cating the in�uence of the environment on gene expression erearetwogeneraltypesofimmuneresponse:innateand is growing rapidly [24]. e relative contribution of nature adaptive. e innate system plays a role in both the initia- and nurture to disease pathogenesis is provided by studies tion and the progression of MS by in�uencing the effector ofgeneticallyidenticaltwinsshowingMSconcordancerates functionofTandBcells[42].us,forexample,throughthe of only 30% [25]. A series of recent genomic studies have activationofspeci�c(mainlytoll-like)receptorsinanantigen con�rmed a central role of the immune system in the nonspeci�cmanner,dendriticcellsbecomesemimatureand pathogenesis of MS, with the MHC class II association now induce regulatory T cells to produce inhibitory cytokines mapped to the HLA-DRB5∗0101-HLA-DRB1∗1501-HLA- such as IL-10 or tumour necrosis factor-𝛾𝛾. As the dendritic DQA1∗0102-HLA-DQB1∗0602 extended haplotype [26– cells mature, they polarize CD4 T cells to differentiate into 29]. Currently, the major environmental factors associated 1, 2, or 17 phenotypes; it is the 1 phenotype that with MS are the Epstein-Barr virus (EBV) seropositivity, promotesin�ammation. cigarettesmoking,andlowplasmaconcentrationsofvitamin eadaptiveresponseisinitiatedbythepresentationofa D3[20,30–33]. speci�c antigen to T lymphocytes by the antigen-presenting cells (APCs). ese APCs include B cells, dendritic cells, microglia, and macrophages. Several types of T cells can 2.TheBlood-CNSBarrier be activated by APCs and initiate the adaptive immune e blood-CNS barrier (BCNSB) is a dynamic and complex response. e key T cells involved are 1, 2, and 17. cellularsystemthatseparatestheCNSfromthebloodstream. 1cellssecreteproin�ammatorycytokines(e.g.,interferon- It does this by strictly controlling the exchange of both 𝛾𝛾 andIL-12),asdo17cells(IL-17,IL-21,IL-22,andIL-26). cells and molecules between the two compartments [34– By contrast, 2 cells secrete anti-in�ammatory cytokines 36]. e largest surface area for exchange is the blood- (e.g.,IL-4andIL-13).RegulatoryTcells,anotherCD4 T-cell brain barrier (BBB), which separates the bloodstream and type,regulateeffector1,2,and17cells.Inadditionto + + + the brain. Its sister barrier, the blood-spinal cord barrier CD4 T-cells,CD8 TcellsmediatethesuppressionofCD4 (BSCB),separatesthebloodstreamandthespinalcord.ere T-cellproliferationthroughthesecretionofperforin,whichis is also an epithelial cell barrier separating the bloodstream cytotoxictoCD4 Tcellsandthusleadstotheirinactivation and the cerebrospinal �uid (CS�) at the choroid plexus and [43,44]. CardiovascularPsychiatryandNeurology 3 (a) (b) (c) (d) (e) (f) Microglia and macrophages Demyelination attack oligodendrocytes and Self-reactive T and NK cells myelin sheaths Proinflammatory Impaired axonal mediators energy metabolism Clonal expansion Neuronal death (g) F1:eroleofcelladhesionmoleculesinthemovementofactivatedTcellsandnaturalkillercellsacrosstheblood-CNSbarrier.(a) Tethering through the interaction of glycosylated PSGL-1 on leukocytes and P-selectin on endothelial cells. (b) Rolling of leukocytes along endothelialcells.(c)Integrinactivationonleukocytes.(d)Firmadhesionthroughtheinteractionof𝛼𝛼 4𝛽𝛽1-integrinandvascularcelladhesion molecule-1 expressed on the endothelial cell layer. (e) Paracellular movement of immune cells into CNS parenchyma (extravasation). (f) Presence of leukocytes in CNS parenchyma. (g) Once in CNS parenchyma, leukocytes increase in number by clonal expansion and then attack the entire supramolecular complex of myelin. is includes (i) a critical antibody response to various myelin proteins and lipids, (ii) initiationofthecomplementcascadeandTandnaturalkillercellattackofcertainkeyportionsofvariousmyelinantigensand(iii)releaseof cytokines,notablytumournecrosisfactor,whichstimulatesmacrophages,microgliaandastrocytes,toproducenitricoxide[45]. 4.TheBCNSBandtheImmuneSystem adhesion(binding),and(iv)extravasationacrosstheBCNSB. isinvolvesthebindingofadhesionmoleculeswithrespec- It was once thought that the CNS was completely isolated tive ligands (Figure 1). e capture and rolling of immune from the immune system and so was “immunologically cells, such as leukocytes, is mediated by the selectin family privileged.”However,itisnowrecognizedthatthisseparation of adhesion molecules and their sulfated, sialylated, and is incomplete since immunological surveillance of the CNS fucosylated glycoprotein ligands. Selectins exist in 3 forms: hasbeenshown tooccur routinely; italso appearstovary P, E, and L. L-selectin is localized on leucocytes, whereas with age and brain region. us, rather than regarding it as E-selectin and P-selectin are found on the endothelium. Of immunologicallyprivileged,theCNSmaymoreaccuratelybe these, the most efficient tethering molecules are P-selectin describedasimmunologicallyspecialized[46,47]. and L-selectin, with L-selectin playing a primary role in e movement of immune cells from the bloodstream lymphoid tissues and P-selectin in other tissues. P-selectin into CNS parenchyma occurs through a sequential and is localized in the Weibel-Palade bodies of endothelial cells coordinated process involving (i) tethering, (ii) rolling, (iii) and𝛼𝛼-granulesofplatelets.Itisrapidlytranslocatedtothecell 4 CardiovascularPsychiatryandNeurology surfaceinresponsetoavarietyofin�ammatorystimulisuch myelinandoligodendrocytesandculminatesinneuronalloss asoxidizedlipoproteins,lipopolysaccharides,andthrombin. byamechanismthatisnotyetclear[65,66]. e main counter ligand is P-selectin glycoprotein ligand- Evidence indicating that the T lymphocytes speci�c for 1 (PSGL-1), a heavily glycosylated sialomucin expressed myelinantigensinitiateanin�ammatoryreactionintheCNS on most leukocytes. Binding takes place, under dynamic isprimarilyderivedfromstudiesofallergicencephalomyeli- conditionstosubstantiallyslowleukocytemovementrelative tis (EAE), a CD4 T-cell-mediated animal (mainly rodent) tomeanblood�ow,asthesecellsrollalongtheendothelium. model of MS. It involves inducing spinal cord in�ammation In vivo studies using mice de�cient in PSGL-1 have shown byinoculationwithhumanspinalcord[67–69]. that PSGL-1 is the predominant, if not the only, P-selectin ere is good evidence to indicate that the BCNSB ligand expressed during in�ammation. e function of plays a pivotal role in the pathophysiology of MS from PSGL-1iscloselylinkedtoitsposttranslationalglycosylation, studies showing that, in EAE, antibodies against 𝛼𝛼4-𝛽𝛽 1- which is mediated by the Golgi enzyme core 2 b1,6-N- integrin,butnotantibodiesagainstnumerousotheradhesion acetylglucosaminyltransferase (C2GnT). C2GnT is responsi- receptors, prevented the accumulation of leukocytes in the ble for the synthesis of speci�c carbohydrate determinants CNS and the development of EAE [70]. Recognition of the on PSGL-1, including a 2,3-sialylated and a 1,3-fucosylated signi�canceofthisdataleddirectlytotheinitiationofhuman core2decoratedO-glycanscarryingthesialylLewisX(sLex) studies with a humanized monoclonal antibody to 𝛼𝛼4-𝛽𝛽 1- motifasacappinggroup[48–51]. integrin (natalizumab) in pwMS [71]. In a recent systematic einteractionbetweenP-selectinandPSGL-1thusleads analysisofavailabledatafrommultiplephaseIIIclinicaltrials tothecaptureofactivatedleukocytesontotheinsidesurface involving a total of 2,223 people with RRMS, natalizumab of blood vessels but is not sufficiently strong to �x leuko- was found to reduce (i) the number of participants who cytes to the vessel wall. e anchoring of rolling leukocytes experienced relapses, (ii) the number of individuals who is achieved by the interaction between very late antigen- progressed at 2 years, and (iii) MRI lesion activity [72]. 4 (VLA-4, 𝛼𝛼4𝛽𝛽1-integrin) and vascular adhesion molecule Blocking the interaction between VLA-4 (𝛼𝛼-4𝛽𝛽1-integrin) (VCAM-1) [52]. Once anchored into position, leukocytes andVCAM-1thereforehastherapeuticefficacyinbothEAE then move across (extravasate) the BCNSB through tiny andMS. spaces in the endothelium into CNS parenchyma [53, 54]. Blocking the interaction between PSGL-1 with its Normally, these cells then mount an attack on infectious endothelialligandP-selectinisanotherpotentialapproachto agentswithintheCNSbut,inthecaseofMS,theyattackhost MS pharmacotherapy [73]. However, this rationale has been cells[3,35,53,55]. questioned because it has been shown that anti-P-selectin antibodies,andPSGL-1andP-selectingeneticde�ciency,had noimpactontheincidence,severity,ordevelopmentofEAE [53, 73–76]. Nonetheless, the rationale for targeting PSGL- 5.TheRoleoftheBCNSBin 1orP-selectionis supported bydataobtained fromhuman thePathophysiologyofMS + + tissues showing that (i) CD8 , but not CD4 , lymphocytes e pathophysiology of MS is characterized by multifocal from pwMS displayed increased rolling on P-selectin using intravital microscopy, (ii) anti-PSGL-1 antibodies block the demyelination and neuronal loss, which probably occurs as a consequence of the movement of activated immune cells recruitment of CD8 cells in brain vessels of pwMS [77]; into the CNS. is requires passage through the BCNSB. (iii)increasednumbersofcirculatingCD4 Tcellswithhigh levelsofPSGL-1werefoundinpwMSpatients,and(iv)these OnceleukocytesareintheCNS,theymultiplybyclonaland oligoclonal expansion, a process that is ampli�ed by proin- T cells had an enhanced ability to migrate across human �ammatory mediators (principally cytokines) through the brain endothelial cells in vitro [78]. In light of these human recruitment of naive microglia and mediated by IFN-𝛾𝛾 and studies, it does seem that the interaction of selectins and IL-12[56,57].isleadstotheprincipalpathologicallesion PSGL-1 probably does play a key role in the pathology of ofMS,thescleroticplaque,whichcanbeseenpostmortem(by MS. e failure of blocking the interaction between PSGL- microscopyofstainedtissue)andintheintactbrain(byMRI 1andP-selectintoimpactthedevelopmentofEAEmaywell imaging) [58–60]. Plaques grow slowly by radial expansion, be attributable to the fact that EAE is mediated by CD4 T + + cells.isisbecauseCD8 ,butnotCD4 ,lymphocytesfrom as focal brain in�ammation fades into di�use parenchymal microglialactivationandresultsinextensiveabnormalitiesin pwMSdisplayedincreasedrollingonP-selectin[77]. normalappearingwhitematter[61].Withtime,theseplaques BCNSB disruption, which is partly mediated by CD8 cells, permits the movement of more leukocytes into the lead to the breakdown of the BCNSB, partly through the action of interleukins 17 and 22. BCNSB disruption permits CNS where they contribute to the loss of both myelin themovementofmoreleukocytesintotheCNSparenchyma, and oligodendrocytes and culminates in neuronal loss by which then leads to multifocal perivascular in�ltrates, pre- mechanismthatisnotyetclear[3,35,43,53,55,65,66]. dominantly T cells and macrophages [36, 62–64]. It is this movement of activated and committed leukocytes from the 6.TheBCNSBandMSDrugsand peripheralcirculationthroughtheBCNSBandintotheCNS DrugCandidates that is the most critical step in the formation of MS lesions. OnceintheCNS,thesecellspropagateandtriggerasequelae Asshownin Table 1, most MS medicines are immunomod- of neuroin�ammatory change that leads to the loss of both ulatory agents, the �rst of which were 𝛽𝛽-interferon (IFN 𝛽𝛽) CardiovascularPsychiatryandNeurology 5 𝜇𝜇 𝜇𝜇 𝜇𝜇 𝜇𝜇 𝛽𝛽 𝛼𝛼 𝛽𝛽 𝛽𝛽 T1:Drugsapprovedforthetreatmentofmultiplesclerosis[3]. Brand(andgeneric)name Mechanismofaction Routeofadministration(dose) Locationofmoleculartarget erapeuticefficacy Avonex:onceaweek,i.m.(30g). Suppressionof1andenhancementof2 Reducedrelapserateand IFN-1a(AvonexandRebif) Rebif:threetimesaweek,subcutaneous Circulatingcompartment immuneresponse MRIlesions (44g) Betaseron:everyotherday,subcutanous Suppressionof1andenhancementof2 (250 g) Reducedrelapserateand IFN-1b(BetaseronandExtavia) Circulatingcompartment immuneresponse Extavia:threetimesaweek, MRIlesions subcutanous(250g) Tolerizationwithmyelin-likeantigensand Reducedrelapserateand Glatirameracetate(Copaxone) Everyday,subcutanous(20mg) Circulatingcompartment modulationofautoreactiveTcells MRIlesions Fourtimesayear,intravenous.e ReducedrelapseandMRI InhibitionoftheproliferationofTcells,B Mitoxantrone(Novantrone) lifetimecumulativedoseislimitedto Circulatingcompartment lesionsanddisease cells,andmacrophages 8–12dosesover2-3years(140mg) progression Ahumanizedmonoclonalantibodyto ReducedrelapseandMRI 4-1-integrinthatpreventsthemovement Everyfourweeksbyintravenous Natalizumab(Tysabri) Circulatingcompartment lesionsanddisease ofleukocytesfromthebloodstreamintothe infusion(300mg) progression CNS Reductioninthenumberoflymphocytesin thebloodbypreventingtheiregressfrom Reducedrelapserateand Fingolimod(Gilenya/Gilenia) Everyday,oral(0.5mg) Circulatingcompartment lymphnodesthroughmodulationofthe MRIlesions sphingosine-1-phosphatereceptor1 Animmunomodulatorwith anti-in�ammatoryproperties,probably Reducedrelapserateand Teri�unomide(Aubagio) Everyday,oral(7or14mg) Circulatingcompartment throughinhibitionofdihydroorotate MRIlesions dehydrogenase Dalfampridine(Ampyra) Potassiumchannelblockade Twiceaday(10mg) CNSandPNS Improvedwalkingspeed CannabinoidCB1andCB2receptor Nabiximols(Sativex) Oromucosalspray(≤12spraysperday) CNS Reducedspasticity agonism Bloodplasmaandlymph�uid.BCNSB:blood-centralnervoussystembarrier�CNS:centralnervoussystem�PNS:peripheralnervoussystem�:Thelpercell. 6 CardiovascularPsychiatryandNeurology drugs. IFN𝛽𝛽s are produced by expression in either Chinese agents.iswouldincludeP-selectin-PSGL-1blockersasan hamster ovary cells (IFN𝛽𝛽-1a) or in Escherichia coli (IFN𝛽𝛽- adjunct to both natalizumab and 𝛼𝛼4-𝛽𝛽1-integrin blocking 1b).Otherapprovedimmunomodulatorydrugsincludeglati- agents with a shorter half-life than natalizumab, such as �rategrast(seebelow). rameracetate(Copaxone),arandompolymeroffouramino acids (L-glutamic acid, L-lysine, L-alanine, and L-tyrosine) Fingolimod (a structural analogue of sphingosine) was found in myelin basic protein, and natalizumab. All of the the �rst small molecule immunomodulatory MS drug to drugs are biologics and so have to be administered by reach the market. Following its phosphorylation, it acts by injection.eyaretoolargetocrosstheBCNSBsinceBCNSB mimickingsphingosine-1-phosphate(S1P)andbindstoS1P permeation is restricted to compounds that are moderately receptors on lymphocytes causing their downregulation. In + + lipophilic and with a molecular weight of less than 450Da the absence of S1P receptor signaling, CD4 , CD8 T cells [41,79]. and B cells are unable to move from secondary lymphoid e molecular target of IFN𝛽𝛽 drugs glatiramer acetate tissue, which substantially reduces the number of lympho- and natalizumab is in the circulating compartment (blood cytes in the blood. erefore, fewer activated leukocytes plasma and lymph �uid) and so BCNSB penetration is are available for movement into the CNS [82]. In people not required in order to achieve therapeutic efficacy. is with RRMS, it has been shown to reduce (i) relapse rate, makes MS unusual in the �eld of CNS medicines research (ii) MRI lesions, (iii) brain-lesion activity, and (iv) loss of as pharmacotherapy for CNS disorders normally requires brain volume, as measured by MRI in comparisons with BCNSB permeation [41]. e emergence of small molecule both placebo and IFN𝛽𝛽-1a. It gained regulatory approval immunomodulatory drugs permits oral administration, from the FDA in 2010 (as Gilenya) and the European which side-steps the difficulties associated with injectable Medicines Agency (EMA) the following year (as Gilenia) biologics,includingthegenerationofneutralizingantibodies [3, 82]. Fingolimod crosses the BCNSB and therefore has and poor drug compliance [3]. However, compounds with thepotentialtointeractwithcentralneuronsandcauseCNS a low molecular weight are much more likely to cross the effects[83]. BCNSBandinteractwithcentralneuronsandpossiblycause Teri�unomide (Aubagio) gained FDA and EMA regula- CNSsideeffects[41]. tory approval for the treatment of RRMS in 2012. It is an Natalizumab gained FDA approval in 2004 as a �rst-line active metabolite of the rheumatoid arthritis drug le�uno- treatment of pwMS with highly active RRMS and a second- mide and inhibits the mitochondrial enzyme dihydrooro- line treatment for pwMS failing to respond to IFN𝛽𝛽 drugs. tate dehydrogenase and thus reduces pyrimidine synthesis. However, its human use was suspended in 2005 because of Because the production of activated T cells largely depends two reports of progressive multifocal leukoencephalopathy on de novo pyrimidine synthesis, pyrimidine depletion is (PML).isisasevereandoenfataldemyelinatingdisorder thought to result in the inhibition of immune cell pro- oftheCNScausedbyalyticinfectionofoligodendrocytesby liferation [84, 85]. On the basis of �ve phase III studies, the JC virus and is characterized by progressive damage of teri�unomideappearstobeefficaciouswithlittleevidenceof white matter. Natalizumab was reintroduced in the United serious adverse events [3].However,itstaysin thebodyfor States, with a black-box warning of PML and approved in uptotwoyears(distributedpredominantlyintheperiphery) the European Union in 2006 aer no additional cases of and may cause liver damage and birth defects. ere is little PML were identi�ed in previously treated patients. e risk evidencetoindicatethatteri�unomidecrossestheBCNSBto of developing PML is substantially reduced by (i) limiting entertheCNS[86]. treatment duration to two years (ii) excluding pwMS taking ere are a number of other low molecular weight immunosuppressivedrugs,and(iii)clinicalvigilance,includ- compoundsthatareinphaseIIIclinicaltrialsorundergoing ingdemonstrationoftheabsenceofanti-JCvirusantibodies regulatory review for the treatment of RRMS. ese are inserumpriortothecommencementoftreatment[80,81]. describedbelow. In two EAE models (C57BL/6 model, and a pertussis (i) Dimethyl fumarate (BG-12) is the methyl ester of toxin-modi�ed model in SJL/J mice), pretreatment with fumaricacid,anintermediateinthetricarboxylicacid blocking antibodies to both 𝛼𝛼4-𝛽𝛽1-integrin and P-selectin cycle.emechanismbywhichtherapeuticefficacyis reduced �rm adhesion of leukocytes to a similar extent� achievedisnotclear,althoughthereisdatatoindicate theseantibodiesalsohadgreaterefficacywhengiventogether thatfumaratetreatmentinducesIL-4-producing2 than when given separately. Despite evidence of blockade of cellsandgeneratestypeIIdendriticcellsthatproduce leukocyte recruitment, no behavioral bene�t was observed IL-10 instead of IL-12 and IL-23. Dimethyl fumarate with either anti-selectin antibodies or genetic deletion of P- isprobablytoohydrophilictocrosstheBCNSB. selectin in eitherEAE of the models. By contrast, antibodies (ii) Laquinimodisthoughttoactbyshiingtheimmune to 𝛼𝛼 4-𝛽𝛽1-integrin delayed the behavioural onset of EAE. responsefrom1to2.Inexperimentalstudies,it e time of onset of EAE was further delayed when 𝛼𝛼4- crosses the BCNSB and so has the potential to cause 𝛽𝛽1-integrin antibodies were combined with P-selectin anti- CNSsideeffects[3]. bodies. Combination treatment also reduced the severity of EAE[73].isprovidesacompellingrationaleforcombining (iii) Firategrast is a small molecule 𝛼𝛼 4-𝛽𝛽-integrin antag- compounds that block the interaction between P-selectin onist that has demonstrated efficacy on imaging andPSGL-1with𝛼𝛼 4-𝛽𝛽1-integrinblockingagentsinorderto endpoints in a phase II study of people with RRMS improve the bene�t/risk pro�le of monotherapy with such [87]. It has a molecular weight (MW) in excess of CardiovascularPsychiatryandNeurology 7 450Da (its MW is 499Da) which is not compatible relativelyfrequentlybutareusuallymildtomoderate withgoodBCNSBpenetration,buthasotherphysic- in intensity and rarely require drug discontinuation ochemical properties (such as log P and the number [98]. ofhydrogendonorsandacceptors)thatareconsistent with BCNSB penetration [41]. Like natalizumab, 7.Conclusions �rategrast indirectly targets the BCNSB by blocking theinteractionbetween𝛼𝛼 4-𝛽𝛽1-integrinonleukocytes Unlike nearly all other blood vessels in the body, the andcelladhesionmoleculesonendothelialcellsofthe endothelial cells of the BCNSB are bound together by tight BCNSB. With �rategrast, there is a reduced liability junctions. is means that a neuroactive compound needs to cause PML as it has a much shorter half-life than to take a transcellular route across the BCNSB in order to natalizumab. entertheCNS.esetightjunctions,coupledwithnumerous efflux transporters and metabolizing enzymes, constitute a In addition to oral immunomodulatory drugs and drug formidable barrier to the movement of both molecules and candidates, two orally available medicines that treat speci�c cellsfromthebloodstreamintotheCNS.eBCNSBplaysa symptomsofMShaverecentlyenteredthemarket.eseare roleinMSanditstreatmentatthreelevels. describedbelow (i) Pathophysiology. e movement of activated leuko- (i) Ampyra,whichisanextendedreleasetabletcontain- cytes across the BBB is a key event in the patho- ing dalfampridine. Dalfampridine is the broad spec- physiology of MS. Once in the brain, these cells trum potassium channel blocker 4-aminopyridine. targetepitopesonmyelin,whichinitiatesacascadeof It works by extending the action potential at both neuroin�ammation that leads to loss of myelin. is axons and nerve terminals, which leads to increased leadstoBCNSBbreakdown(whichcanbevisualized releaseofneurotransmitterandthusimprovesmotor by gadolinium-enhanced T -weighted MRI scans) function in demyelinated or functionally impaired andtheformationofplaques. neurons.Itgainedapprovalonthebasisofdatafrom (ii) Drug-induced pathophysiology. Natalizumab blocks two phase III clinical trials that demonstrated that immunological surveillance of the CNS, leaving the Ampyra(10mgtwicedaily)improvedwalkingspeed CNS immunocompromised. A detrimental conse- (measured by the timed 25-foot walk) by an average quenceofthisisthereactivationoftheJCvirusinthe of25%.oughmodest,thisimprovementwasasso- brainwhichcanthenleadtoPML. ciated with a reduction in ambulatory disability in pwMS[88–90].However,onlyone-thirdofthepwMS (iii) MSpharmacotherapy.MostMSmedicinesarebiolog- whoreceivedthedrugwereconsistentresponders. icaldrugsandsotheirlargesizepreventstheirmove- ment across the BCNSB. However, the emergence Dalfampridine has a poor therapeutic/risk ratio as of small molecule immunomodulatory drugs will potassium channels are intrinsic to normal function, increase the probability of such compounds entering particularly in the heart and the CNS. us, adverse the CNS, which will increase the risk of CNS side events were mainly related to stimulatory effects on effects[41].SomeMSdrugs(suchasnabiximolsand the nervous system. e most commonly reported dalfampridine) are centrally acting and so there is a side effects were MS relapse and epileptic seizures requirementforthemtocrosstheBCNSBinorderto [89]. is is consistent with dalfampridine crossing achievethedesiredtherapeuticeffect. the BBB, a conclusion supported by studies showing accumulation of dalfampridine in both the brain ISF IFN𝛽𝛽 drugs and glatiramer acetate have dominated the andCSFcompartmentsfollowingsystemicdosingin MS market for over a decade. is dominance is set to rats [91, 92]. Even so, an analysis of multiple pub- change with (i) the introduction of natalizumab, which lished clinical studies indicates that adverse events targets the interaction between leukocytes and the BCNSB are dose related, mild to moderate and transient, and has an impressive e�cacy pro�le; (ii) the launch of particularly at the low dose of 10mg twice daily [93, three oral immunomodulatory drugs (�ngolimod, dimethyl 94]. fumarate, and teri�unomide), with more (e.g., laquinimod (ii) Nabiximols (Sativex) is a cannabis-based oral spray and �rategrast) in late stage development; (iii) a number of containing a de�ned quantity of speci�c canna- immunomodulatory monoclonal antibodies (alemtuzumab, binoids, particularly tetrahydrocannabinol and daclizumab,andocrelizumab)abouttoenterthemarket;and cannabidiol, which are cannabinoid CB1 and CB2 (iv)theemergenceofdrugstargetingsymptommanagement, receptoragonists,respectively[95,96].Sinceitactson including motor dysfunction (dalfampridine) and spasticity CNS neurons, BCNSB penetration is essential. 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Multiple Sclerosis and the Blood-Central Nervous System Barrier

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Copyright © 2013 Alan M. Palmer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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HindawiPublishingCorporation CardiovascularPsychiatryandNeurology Volume2013,ArticleID530356,10pages http://dx.doi.org/10.1155/2013/530356 ReviewArticle AlanM.Palmer MSerapeuticsLtd.,BeecheyHouse,87ChurchStreet,Crowthorne,BerksRG457AW,UK CorrespondenceshouldbeaddressedtoAlanM.Palmer;alan.palmer@mstherapeutics.com Received22October2012;Revised25December2012;Accepted25December2012 AcademicEditor:GjumrakchAliev Copyright©2013AlanM.Palmer. is is an open access article distributed under the Creative Commons Attribution License, whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. e central nervous system (CNS) is isolated from the blood system by a physical barrier that contains efflux transporters and catabolicenzymes.isblood-CNSbarrier(BCNSB)playsapivotalroleinthepathophysiologyofmultiplesclerosis(MS).Itbinds andanchorsactivatedleukocytestopermittheirmovementacrosstheBCNSBandintotheCNS.Oncethere,theseimmunecells target particular self-epitopes and initiate a cascade of neuroin�ammation, which leads to the breakdown of the BCNSB and the formation of perivascular plaques, one of the hallmarks of MS. Immunomodulatory drugs for MS are either biologics or small molecules, with only the latter having the capacity to cross the BCNSB and thus have a propensity to cause CNS side effects. However,BCNSBpenetrationisadesirablefeatureofMSdrugsthathavemoleculartargetswithintheCNS.esearenabiximols and dalfampridine, which target cannabinoid receptors and potassium channels, respectively. Vascular cell adhesion molecule-1, presentonendothelialcellsoftheBCNSB,alsoservesasadrugdiscoverytargetsinceitinteractswith𝛼𝛼4-𝛽𝛽1-integrinonleucocytes. eMSdrugnatalizumab,ahumanizedmonoclonalantibodyagainst𝛼𝛼4-𝛽𝛽1-integrin,blocksthisinteractionandthusreducesthe movement of immune cells into the CNS. is paper further elaborates on the role of the BCNSB in the pathophysiology and pharmacotherapyofMS. but with insu�cient evidence for a de�nitive diagnosis of 1.Introduction MS[9,10].isisreferredtoasclinicallyisolatedsyndrome Multiple sclerosis (MS) is an acquired autoimmune disease and, in most cases (80% aer 20 years), progresses to RRMS that affects both the brain and the spinal cord leading to a [11]. At the other end of the RRMS continuum is secondary variety of symptoms, including changes in motor function, progressive MS (SPMS). e majority of those with RRMS senseperception,andmentalfunction,alongwithfatigue[1– converttoSPMSwithintwoorthreedecades.Ithasasimilar 3].ediseasepresentsindifferentformsthatfollowdistinct progressive and irreversible course to that of PPMS [12– patterns of evolution and rates of disability progression [4]. 14]. A �nal subset, which resembles RRMS, is progressive e most common form is relapsing-remitting MS (RRMS), relapsing MS, which affects less than 5% of pwMS. It is whichaffectsabout85%ofpeoplewithMS(pwMS),ismore characterizedbyasteadydeclineinneurologicfunctionand common in females than males (by a ratio of 2 to 1), and clearsuperimposedexacerbations[4]. has an average age at diagnosis of 29 years [5]. RRMS is MRIplaysanincreasinglyimportantroleinthediagnosis characterized by acute attacks (relapses) followed by partial andmanagementofMS. Itisalso routinelyused asthepri- or full recovery (remission) and contrasts with primary mary endpoint in proof-of-concept clinical trials evaluating progressive MS (PPMS), which affects about 10–15% of potentialnewdrugsforMS,andasthesecondaryendpointin pwMS,isdiagnosed(onaverage)atage40,hasnogenderbias, de�nitivephaseIIItrials[15].MRIscansdistinguishfatfrom and is characterized by a steady and irreversible progression water.InT -weightedimageswaterisdarkerandfatbrighter, offunctionalimpairments[6–8].esetwoformsofMSalso whereastheoppositeisthecase in T -weighted scans. Since differ in their onset as PPMS begins insidiously, whereas myelinispredominantlylipid(andthushydrophobic),areas the harbinger of RRMS is usually a transient impairment ofdemyelinationholdmorewaterandsoshowupaseithera in motor or sensory function, together with white matter brightwhitespot(inaT -weightedscan)oradarkenedarea abnormalitiesshownbymagneticresonanceimaging(MRI), (in a T -weighted scan). e sensitivity of the T -weighted 1 1 2 CardiovascularPsychiatryandNeurology scansisoenenhancedbytheuseofcontrastagents,suchas the arachnoid villi. Both the BBB and the BSCB comprise gadoliniumdiethylenetriaminepentaaceticacid.Gadolinium theendothelialcellsofCNSbloodvessels,alongwithathick enhancement permits direct visualization of breaches in basement membrane and astrocytes. ey display a unique the BCNSB that accompany acute MS and so is used to phenotype characterized by the presence of endothelial cells visualize the number of new plaques in the CNS (usually thatareconnectedbyanintercellularadhesioncomplex.is the brain) of pwMS. It therefore provides a good measure forms the close contact between the adjacent cells known as of disease activity and helps distinguish between acute (or tightjunctions.isbarrierfunctionoftheBCNSBisfurther active)plaquesandchronic(ornonactive)lesions[16].Inthe enhancedbytherelativepaucityoffenestraeandpinocytotic brain,MSplaquesarecommonlyroundorovoidandrangein vesicles.Collectively,thisresultsinalowlevelofendocytosis sizefromafewmmtomorethan1cmandareoenfoundin and transcytosis, which severely restricts the movement of the brainstem, cerebellum, and periventricular white matter molecules and cells into the CNS via the transcellular route [17–19]. [34]. Plaques are regions of demyelination and neuronal loss. e BCNSB has two further barrier elements: (i) a ey occur as a consequence of the movement of activated metabolic barrier that contains a complex array of enzymes immune cells from the bloodstream into the brain or spinal (including acetylcholinesterase, alkaline phosphatase, 𝛾𝛾 - cord (or both) across the blood-CNS barrier (BCNSB) [20]. glutamyl transpeptidase, and monoamine oxidases) that e cascade of in�ammatory change is probably initiated by degrade different chemical compounds thus altering their + + autoreactive T-cells, particularly CD4 and CD8 T helper pharmacologicalactivityand(ii)atransportbarrierthatcon- ()cells.CD4 cellsrecognizeantigensthatarepresentedby tainsavarietyofeffluxtransporters,includingP-glycoprotein majorhistocompatibilitycomplex(MHC)moleculesonspe- andbreastcancerresistanceprotein[34,37,38]. cializedantigen-presentingcellsandpresentthemtospeci�c TightjunctionsarethecriticalcomponentoftheBCNSB T cell receptors [21]. e activation of immune cells by an astheycontrolparacellulardiffusionandmaintainthestruc- tural and functional polarity of the specialized endothelial autoantigen leads the CD4 cells to commence pathological destruction of cells of self, particularly myelinated CNS cells of the BBB and BSCB. us, the BCNSB contributes to neurons. e most prominent candidates for autoantigens thehomeostasisof theparenchymaofthebrainandspinal are proteins present in myelin, such as myelin basic protein, cordandprovidesprotectionagainstmanytoxiccompounds myelinoligodendroglialglycoprotein,neurofascinandprote- and pathogens [34, 36, 39]. Indeed, the BCNSB is largely olipid protein. Other candidates include stress proteins such impermeabletocompoundsthatarenotlipophilicandhavea as B crystallin, which is found in the myelin sheath aer molecularweightgreaterthan450Da.ispresentsamajor activationviathein�ammatoryresponse[22,23]. challengeforCNSdrugdiscovery[40,41]. ecause ofMS isnotyetunderstood, butitisknown thatdozensofgeneticvariationsactinconcertwithenviron- 3.TheRoleoftheImmuneSysteminMS mentalfactorstotriggerdiseasepathogenesis.Evidenceindi- cating the in�uence of the environment on gene expression erearetwogeneraltypesofimmuneresponse:innateand is growing rapidly [24]. e relative contribution of nature adaptive. e innate system plays a role in both the initia- and nurture to disease pathogenesis is provided by studies tion and the progression of MS by in�uencing the effector ofgeneticallyidenticaltwinsshowingMSconcordancerates functionofTandBcells[42].us,forexample,throughthe of only 30% [25]. A series of recent genomic studies have activationofspeci�c(mainlytoll-like)receptorsinanantigen con�rmed a central role of the immune system in the nonspeci�cmanner,dendriticcellsbecomesemimatureand pathogenesis of MS, with the MHC class II association now induce regulatory T cells to produce inhibitory cytokines mapped to the HLA-DRB5∗0101-HLA-DRB1∗1501-HLA- such as IL-10 or tumour necrosis factor-𝛾𝛾. As the dendritic DQA1∗0102-HLA-DQB1∗0602 extended haplotype [26– cells mature, they polarize CD4 T cells to differentiate into 29]. Currently, the major environmental factors associated 1, 2, or 17 phenotypes; it is the 1 phenotype that with MS are the Epstein-Barr virus (EBV) seropositivity, promotesin�ammation. cigarettesmoking,andlowplasmaconcentrationsofvitamin eadaptiveresponseisinitiatedbythepresentationofa D3[20,30–33]. speci�c antigen to T lymphocytes by the antigen-presenting cells (APCs). ese APCs include B cells, dendritic cells, microglia, and macrophages. Several types of T cells can 2.TheBlood-CNSBarrier be activated by APCs and initiate the adaptive immune e blood-CNS barrier (BCNSB) is a dynamic and complex response. e key T cells involved are 1, 2, and 17. cellularsystemthatseparatestheCNSfromthebloodstream. 1cellssecreteproin�ammatorycytokines(e.g.,interferon- It does this by strictly controlling the exchange of both 𝛾𝛾 andIL-12),asdo17cells(IL-17,IL-21,IL-22,andIL-26). cells and molecules between the two compartments [34– By contrast, 2 cells secrete anti-in�ammatory cytokines 36]. e largest surface area for exchange is the blood- (e.g.,IL-4andIL-13).RegulatoryTcells,anotherCD4 T-cell brain barrier (BBB), which separates the bloodstream and type,regulateeffector1,2,and17cells.Inadditionto + + + the brain. Its sister barrier, the blood-spinal cord barrier CD4 T-cells,CD8 TcellsmediatethesuppressionofCD4 (BSCB),separatesthebloodstreamandthespinalcord.ere T-cellproliferationthroughthesecretionofperforin,whichis is also an epithelial cell barrier separating the bloodstream cytotoxictoCD4 Tcellsandthusleadstotheirinactivation and the cerebrospinal �uid (CS�) at the choroid plexus and [43,44]. CardiovascularPsychiatryandNeurology 3 (a) (b) (c) (d) (e) (f) Microglia and macrophages Demyelination attack oligodendrocytes and Self-reactive T and NK cells myelin sheaths Proinflammatory Impaired axonal mediators energy metabolism Clonal expansion Neuronal death (g) F1:eroleofcelladhesionmoleculesinthemovementofactivatedTcellsandnaturalkillercellsacrosstheblood-CNSbarrier.(a) Tethering through the interaction of glycosylated PSGL-1 on leukocytes and P-selectin on endothelial cells. (b) Rolling of leukocytes along endothelialcells.(c)Integrinactivationonleukocytes.(d)Firmadhesionthroughtheinteractionof𝛼𝛼 4𝛽𝛽1-integrinandvascularcelladhesion molecule-1 expressed on the endothelial cell layer. (e) Paracellular movement of immune cells into CNS parenchyma (extravasation). (f) Presence of leukocytes in CNS parenchyma. (g) Once in CNS parenchyma, leukocytes increase in number by clonal expansion and then attack the entire supramolecular complex of myelin. is includes (i) a critical antibody response to various myelin proteins and lipids, (ii) initiationofthecomplementcascadeandTandnaturalkillercellattackofcertainkeyportionsofvariousmyelinantigensand(iii)releaseof cytokines,notablytumournecrosisfactor,whichstimulatesmacrophages,microgliaandastrocytes,toproducenitricoxide[45]. 4.TheBCNSBandtheImmuneSystem adhesion(binding),and(iv)extravasationacrosstheBCNSB. isinvolvesthebindingofadhesionmoleculeswithrespec- It was once thought that the CNS was completely isolated tive ligands (Figure 1). e capture and rolling of immune from the immune system and so was “immunologically cells, such as leukocytes, is mediated by the selectin family privileged.”However,itisnowrecognizedthatthisseparation of adhesion molecules and their sulfated, sialylated, and is incomplete since immunological surveillance of the CNS fucosylated glycoprotein ligands. Selectins exist in 3 forms: hasbeenshown tooccur routinely; italso appearstovary P, E, and L. L-selectin is localized on leucocytes, whereas with age and brain region. us, rather than regarding it as E-selectin and P-selectin are found on the endothelium. Of immunologicallyprivileged,theCNSmaymoreaccuratelybe these, the most efficient tethering molecules are P-selectin describedasimmunologicallyspecialized[46,47]. and L-selectin, with L-selectin playing a primary role in e movement of immune cells from the bloodstream lymphoid tissues and P-selectin in other tissues. P-selectin into CNS parenchyma occurs through a sequential and is localized in the Weibel-Palade bodies of endothelial cells coordinated process involving (i) tethering, (ii) rolling, (iii) and𝛼𝛼-granulesofplatelets.Itisrapidlytranslocatedtothecell 4 CardiovascularPsychiatryandNeurology surfaceinresponsetoavarietyofin�ammatorystimulisuch myelinandoligodendrocytesandculminatesinneuronalloss asoxidizedlipoproteins,lipopolysaccharides,andthrombin. byamechanismthatisnotyetclear[65,66]. e main counter ligand is P-selectin glycoprotein ligand- Evidence indicating that the T lymphocytes speci�c for 1 (PSGL-1), a heavily glycosylated sialomucin expressed myelinantigensinitiateanin�ammatoryreactionintheCNS on most leukocytes. Binding takes place, under dynamic isprimarilyderivedfromstudiesofallergicencephalomyeli- conditionstosubstantiallyslowleukocytemovementrelative tis (EAE), a CD4 T-cell-mediated animal (mainly rodent) tomeanblood�ow,asthesecellsrollalongtheendothelium. model of MS. It involves inducing spinal cord in�ammation In vivo studies using mice de�cient in PSGL-1 have shown byinoculationwithhumanspinalcord[67–69]. that PSGL-1 is the predominant, if not the only, P-selectin ere is good evidence to indicate that the BCNSB ligand expressed during in�ammation. e function of plays a pivotal role in the pathophysiology of MS from PSGL-1iscloselylinkedtoitsposttranslationalglycosylation, studies showing that, in EAE, antibodies against 𝛼𝛼4-𝛽𝛽 1- which is mediated by the Golgi enzyme core 2 b1,6-N- integrin,butnotantibodiesagainstnumerousotheradhesion acetylglucosaminyltransferase (C2GnT). C2GnT is responsi- receptors, prevented the accumulation of leukocytes in the ble for the synthesis of speci�c carbohydrate determinants CNS and the development of EAE [70]. Recognition of the on PSGL-1, including a 2,3-sialylated and a 1,3-fucosylated signi�canceofthisdataleddirectlytotheinitiationofhuman core2decoratedO-glycanscarryingthesialylLewisX(sLex) studies with a humanized monoclonal antibody to 𝛼𝛼4-𝛽𝛽 1- motifasacappinggroup[48–51]. integrin (natalizumab) in pwMS [71]. In a recent systematic einteractionbetweenP-selectinandPSGL-1thusleads analysisofavailabledatafrommultiplephaseIIIclinicaltrials tothecaptureofactivatedleukocytesontotheinsidesurface involving a total of 2,223 people with RRMS, natalizumab of blood vessels but is not sufficiently strong to �x leuko- was found to reduce (i) the number of participants who cytes to the vessel wall. e anchoring of rolling leukocytes experienced relapses, (ii) the number of individuals who is achieved by the interaction between very late antigen- progressed at 2 years, and (iii) MRI lesion activity [72]. 4 (VLA-4, 𝛼𝛼4𝛽𝛽1-integrin) and vascular adhesion molecule Blocking the interaction between VLA-4 (𝛼𝛼-4𝛽𝛽1-integrin) (VCAM-1) [52]. Once anchored into position, leukocytes andVCAM-1thereforehastherapeuticefficacyinbothEAE then move across (extravasate) the BCNSB through tiny andMS. spaces in the endothelium into CNS parenchyma [53, 54]. Blocking the interaction between PSGL-1 with its Normally, these cells then mount an attack on infectious endothelialligandP-selectinisanotherpotentialapproachto agentswithintheCNSbut,inthecaseofMS,theyattackhost MS pharmacotherapy [73]. However, this rationale has been cells[3,35,53,55]. questioned because it has been shown that anti-P-selectin antibodies,andPSGL-1andP-selectingeneticde�ciency,had noimpactontheincidence,severity,ordevelopmentofEAE [53, 73–76]. Nonetheless, the rationale for targeting PSGL- 5.TheRoleoftheBCNSBin 1orP-selectionis supported bydataobtained fromhuman thePathophysiologyofMS + + tissues showing that (i) CD8 , but not CD4 , lymphocytes e pathophysiology of MS is characterized by multifocal from pwMS displayed increased rolling on P-selectin using intravital microscopy, (ii) anti-PSGL-1 antibodies block the demyelination and neuronal loss, which probably occurs as a consequence of the movement of activated immune cells recruitment of CD8 cells in brain vessels of pwMS [77]; into the CNS. is requires passage through the BCNSB. (iii)increasednumbersofcirculatingCD4 Tcellswithhigh levelsofPSGL-1werefoundinpwMSpatients,and(iv)these OnceleukocytesareintheCNS,theymultiplybyclonaland oligoclonal expansion, a process that is ampli�ed by proin- T cells had an enhanced ability to migrate across human �ammatory mediators (principally cytokines) through the brain endothelial cells in vitro [78]. In light of these human recruitment of naive microglia and mediated by IFN-𝛾𝛾 and studies, it does seem that the interaction of selectins and IL-12[56,57].isleadstotheprincipalpathologicallesion PSGL-1 probably does play a key role in the pathology of ofMS,thescleroticplaque,whichcanbeseenpostmortem(by MS. e failure of blocking the interaction between PSGL- microscopyofstainedtissue)andintheintactbrain(byMRI 1andP-selectintoimpactthedevelopmentofEAEmaywell imaging) [58–60]. Plaques grow slowly by radial expansion, be attributable to the fact that EAE is mediated by CD4 T + + cells.isisbecauseCD8 ,butnotCD4 ,lymphocytesfrom as focal brain in�ammation fades into di�use parenchymal microglialactivationandresultsinextensiveabnormalitiesin pwMSdisplayedincreasedrollingonP-selectin[77]. normalappearingwhitematter[61].Withtime,theseplaques BCNSB disruption, which is partly mediated by CD8 cells, permits the movement of more leukocytes into the lead to the breakdown of the BCNSB, partly through the action of interleukins 17 and 22. BCNSB disruption permits CNS where they contribute to the loss of both myelin themovementofmoreleukocytesintotheCNSparenchyma, and oligodendrocytes and culminates in neuronal loss by which then leads to multifocal perivascular in�ltrates, pre- mechanismthatisnotyetclear[3,35,43,53,55,65,66]. dominantly T cells and macrophages [36, 62–64]. It is this movement of activated and committed leukocytes from the 6.TheBCNSBandMSDrugsand peripheralcirculationthroughtheBCNSBandintotheCNS DrugCandidates that is the most critical step in the formation of MS lesions. OnceintheCNS,thesecellspropagateandtriggerasequelae Asshownin Table 1, most MS medicines are immunomod- of neuroin�ammatory change that leads to the loss of both ulatory agents, the �rst of which were 𝛽𝛽-interferon (IFN 𝛽𝛽) CardiovascularPsychiatryandNeurology 5 𝜇𝜇 𝜇𝜇 𝜇𝜇 𝜇𝜇 𝛽𝛽 𝛼𝛼 𝛽𝛽 𝛽𝛽 T1:Drugsapprovedforthetreatmentofmultiplesclerosis[3]. Brand(andgeneric)name Mechanismofaction Routeofadministration(dose) Locationofmoleculartarget erapeuticefficacy Avonex:onceaweek,i.m.(30g). Suppressionof1andenhancementof2 Reducedrelapserateand IFN-1a(AvonexandRebif) Rebif:threetimesaweek,subcutaneous Circulatingcompartment immuneresponse MRIlesions (44g) Betaseron:everyotherday,subcutanous Suppressionof1andenhancementof2 (250 g) Reducedrelapserateand IFN-1b(BetaseronandExtavia) Circulatingcompartment immuneresponse Extavia:threetimesaweek, MRIlesions subcutanous(250g) Tolerizationwithmyelin-likeantigensand Reducedrelapserateand Glatirameracetate(Copaxone) Everyday,subcutanous(20mg) Circulatingcompartment modulationofautoreactiveTcells MRIlesions Fourtimesayear,intravenous.e ReducedrelapseandMRI InhibitionoftheproliferationofTcells,B Mitoxantrone(Novantrone) lifetimecumulativedoseislimitedto Circulatingcompartment lesionsanddisease cells,andmacrophages 8–12dosesover2-3years(140mg) progression Ahumanizedmonoclonalantibodyto ReducedrelapseandMRI 4-1-integrinthatpreventsthemovement Everyfourweeksbyintravenous Natalizumab(Tysabri) Circulatingcompartment lesionsanddisease ofleukocytesfromthebloodstreamintothe infusion(300mg) progression CNS Reductioninthenumberoflymphocytesin thebloodbypreventingtheiregressfrom Reducedrelapserateand Fingolimod(Gilenya/Gilenia) Everyday,oral(0.5mg) Circulatingcompartment lymphnodesthroughmodulationofthe MRIlesions sphingosine-1-phosphatereceptor1 Animmunomodulatorwith anti-in�ammatoryproperties,probably Reducedrelapserateand Teri�unomide(Aubagio) Everyday,oral(7or14mg) Circulatingcompartment throughinhibitionofdihydroorotate MRIlesions dehydrogenase Dalfampridine(Ampyra) Potassiumchannelblockade Twiceaday(10mg) CNSandPNS Improvedwalkingspeed CannabinoidCB1andCB2receptor Nabiximols(Sativex) Oromucosalspray(≤12spraysperday) CNS Reducedspasticity agonism Bloodplasmaandlymph�uid.BCNSB:blood-centralnervoussystembarrier�CNS:centralnervoussystem�PNS:peripheralnervoussystem�:Thelpercell. 6 CardiovascularPsychiatryandNeurology drugs. IFN𝛽𝛽s are produced by expression in either Chinese agents.iswouldincludeP-selectin-PSGL-1blockersasan hamster ovary cells (IFN𝛽𝛽-1a) or in Escherichia coli (IFN𝛽𝛽- adjunct to both natalizumab and 𝛼𝛼4-𝛽𝛽1-integrin blocking 1b).Otherapprovedimmunomodulatorydrugsincludeglati- agents with a shorter half-life than natalizumab, such as �rategrast(seebelow). rameracetate(Copaxone),arandompolymeroffouramino acids (L-glutamic acid, L-lysine, L-alanine, and L-tyrosine) Fingolimod (a structural analogue of sphingosine) was found in myelin basic protein, and natalizumab. All of the the �rst small molecule immunomodulatory MS drug to drugs are biologics and so have to be administered by reach the market. Following its phosphorylation, it acts by injection.eyaretoolargetocrosstheBCNSBsinceBCNSB mimickingsphingosine-1-phosphate(S1P)andbindstoS1P permeation is restricted to compounds that are moderately receptors on lymphocytes causing their downregulation. In + + lipophilic and with a molecular weight of less than 450Da the absence of S1P receptor signaling, CD4 , CD8 T cells [41,79]. and B cells are unable to move from secondary lymphoid e molecular target of IFN𝛽𝛽 drugs glatiramer acetate tissue, which substantially reduces the number of lympho- and natalizumab is in the circulating compartment (blood cytes in the blood. erefore, fewer activated leukocytes plasma and lymph �uid) and so BCNSB penetration is are available for movement into the CNS [82]. In people not required in order to achieve therapeutic efficacy. is with RRMS, it has been shown to reduce (i) relapse rate, makes MS unusual in the �eld of CNS medicines research (ii) MRI lesions, (iii) brain-lesion activity, and (iv) loss of as pharmacotherapy for CNS disorders normally requires brain volume, as measured by MRI in comparisons with BCNSB permeation [41]. e emergence of small molecule both placebo and IFN𝛽𝛽-1a. It gained regulatory approval immunomodulatory drugs permits oral administration, from the FDA in 2010 (as Gilenya) and the European which side-steps the difficulties associated with injectable Medicines Agency (EMA) the following year (as Gilenia) biologics,includingthegenerationofneutralizingantibodies [3, 82]. Fingolimod crosses the BCNSB and therefore has and poor drug compliance [3]. However, compounds with thepotentialtointeractwithcentralneuronsandcauseCNS a low molecular weight are much more likely to cross the effects[83]. BCNSBandinteractwithcentralneuronsandpossiblycause Teri�unomide (Aubagio) gained FDA and EMA regula- CNSsideeffects[41]. tory approval for the treatment of RRMS in 2012. It is an Natalizumab gained FDA approval in 2004 as a �rst-line active metabolite of the rheumatoid arthritis drug le�uno- treatment of pwMS with highly active RRMS and a second- mide and inhibits the mitochondrial enzyme dihydrooro- line treatment for pwMS failing to respond to IFN𝛽𝛽 drugs. tate dehydrogenase and thus reduces pyrimidine synthesis. However, its human use was suspended in 2005 because of Because the production of activated T cells largely depends two reports of progressive multifocal leukoencephalopathy on de novo pyrimidine synthesis, pyrimidine depletion is (PML).isisasevereandoenfataldemyelinatingdisorder thought to result in the inhibition of immune cell pro- oftheCNScausedbyalyticinfectionofoligodendrocytesby liferation [84, 85]. On the basis of �ve phase III studies, the JC virus and is characterized by progressive damage of teri�unomideappearstobeefficaciouswithlittleevidenceof white matter. Natalizumab was reintroduced in the United serious adverse events [3].However,itstaysin thebodyfor States, with a black-box warning of PML and approved in uptotwoyears(distributedpredominantlyintheperiphery) the European Union in 2006 aer no additional cases of and may cause liver damage and birth defects. ere is little PML were identi�ed in previously treated patients. e risk evidencetoindicatethatteri�unomidecrossestheBCNSBto of developing PML is substantially reduced by (i) limiting entertheCNS[86]. treatment duration to two years (ii) excluding pwMS taking ere are a number of other low molecular weight immunosuppressivedrugs,and(iii)clinicalvigilance,includ- compoundsthatareinphaseIIIclinicaltrialsorundergoing ingdemonstrationoftheabsenceofanti-JCvirusantibodies regulatory review for the treatment of RRMS. ese are inserumpriortothecommencementoftreatment[80,81]. describedbelow. In two EAE models (C57BL/6 model, and a pertussis (i) Dimethyl fumarate (BG-12) is the methyl ester of toxin-modi�ed model in SJL/J mice), pretreatment with fumaricacid,anintermediateinthetricarboxylicacid blocking antibodies to both 𝛼𝛼4-𝛽𝛽1-integrin and P-selectin cycle.emechanismbywhichtherapeuticefficacyis reduced �rm adhesion of leukocytes to a similar extent� achievedisnotclear,althoughthereisdatatoindicate theseantibodiesalsohadgreaterefficacywhengiventogether thatfumaratetreatmentinducesIL-4-producing2 than when given separately. Despite evidence of blockade of cellsandgeneratestypeIIdendriticcellsthatproduce leukocyte recruitment, no behavioral bene�t was observed IL-10 instead of IL-12 and IL-23. Dimethyl fumarate with either anti-selectin antibodies or genetic deletion of P- isprobablytoohydrophilictocrosstheBCNSB. selectin in eitherEAE of the models. By contrast, antibodies (ii) Laquinimodisthoughttoactbyshiingtheimmune to 𝛼𝛼 4-𝛽𝛽1-integrin delayed the behavioural onset of EAE. responsefrom1to2.Inexperimentalstudies,it e time of onset of EAE was further delayed when 𝛼𝛼4- crosses the BCNSB and so has the potential to cause 𝛽𝛽1-integrin antibodies were combined with P-selectin anti- CNSsideeffects[3]. bodies. Combination treatment also reduced the severity of EAE[73].isprovidesacompellingrationaleforcombining (iii) Firategrast is a small molecule 𝛼𝛼 4-𝛽𝛽-integrin antag- compounds that block the interaction between P-selectin onist that has demonstrated efficacy on imaging andPSGL-1with𝛼𝛼 4-𝛽𝛽1-integrinblockingagentsinorderto endpoints in a phase II study of people with RRMS improve the bene�t/risk pro�le of monotherapy with such [87]. It has a molecular weight (MW) in excess of CardiovascularPsychiatryandNeurology 7 450Da (its MW is 499Da) which is not compatible relativelyfrequentlybutareusuallymildtomoderate withgoodBCNSBpenetration,buthasotherphysic- in intensity and rarely require drug discontinuation ochemical properties (such as log P and the number [98]. ofhydrogendonorsandacceptors)thatareconsistent with BCNSB penetration [41]. Like natalizumab, 7.Conclusions �rategrast indirectly targets the BCNSB by blocking theinteractionbetween𝛼𝛼 4-𝛽𝛽1-integrinonleukocytes Unlike nearly all other blood vessels in the body, the andcelladhesionmoleculesonendothelialcellsofthe endothelial cells of the BCNSB are bound together by tight BCNSB. With �rategrast, there is a reduced liability junctions. is means that a neuroactive compound needs to cause PML as it has a much shorter half-life than to take a transcellular route across the BCNSB in order to natalizumab. entertheCNS.esetightjunctions,coupledwithnumerous efflux transporters and metabolizing enzymes, constitute a In addition to oral immunomodulatory drugs and drug formidable barrier to the movement of both molecules and candidates, two orally available medicines that treat speci�c cellsfromthebloodstreamintotheCNS.eBCNSBplaysa symptomsofMShaverecentlyenteredthemarket.eseare roleinMSanditstreatmentatthreelevels. describedbelow (i) Pathophysiology. e movement of activated leuko- (i) Ampyra,whichisanextendedreleasetabletcontain- cytes across the BBB is a key event in the patho- ing dalfampridine. Dalfampridine is the broad spec- physiology of MS. Once in the brain, these cells trum potassium channel blocker 4-aminopyridine. targetepitopesonmyelin,whichinitiatesacascadeof It works by extending the action potential at both neuroin�ammation that leads to loss of myelin. is axons and nerve terminals, which leads to increased leadstoBCNSBbreakdown(whichcanbevisualized releaseofneurotransmitterandthusimprovesmotor by gadolinium-enhanced T -weighted MRI scans) function in demyelinated or functionally impaired andtheformationofplaques. neurons.Itgainedapprovalonthebasisofdatafrom (ii) Drug-induced pathophysiology. Natalizumab blocks two phase III clinical trials that demonstrated that immunological surveillance of the CNS, leaving the Ampyra(10mgtwicedaily)improvedwalkingspeed CNS immunocompromised. A detrimental conse- (measured by the timed 25-foot walk) by an average quenceofthisisthereactivationoftheJCvirusinthe of25%.oughmodest,thisimprovementwasasso- brainwhichcanthenleadtoPML. ciated with a reduction in ambulatory disability in pwMS[88–90].However,onlyone-thirdofthepwMS (iii) MSpharmacotherapy.MostMSmedicinesarebiolog- whoreceivedthedrugwereconsistentresponders. icaldrugsandsotheirlargesizepreventstheirmove- ment across the BCNSB. However, the emergence Dalfampridine has a poor therapeutic/risk ratio as of small molecule immunomodulatory drugs will potassium channels are intrinsic to normal function, increase the probability of such compounds entering particularly in the heart and the CNS. us, adverse the CNS, which will increase the risk of CNS side events were mainly related to stimulatory effects on effects[41].SomeMSdrugs(suchasnabiximolsand the nervous system. e most commonly reported dalfampridine) are centrally acting and so there is a side effects were MS relapse and epileptic seizures requirementforthemtocrosstheBCNSBinorderto [89]. is is consistent with dalfampridine crossing achievethedesiredtherapeuticeffect. the BBB, a conclusion supported by studies showing accumulation of dalfampridine in both the brain ISF IFN𝛽𝛽 drugs and glatiramer acetate have dominated the andCSFcompartmentsfollowingsystemicdosingin MS market for over a decade. is dominance is set to rats [91, 92]. Even so, an analysis of multiple pub- change with (i) the introduction of natalizumab, which lished clinical studies indicates that adverse events targets the interaction between leukocytes and the BCNSB are dose related, mild to moderate and transient, and has an impressive e�cacy pro�le; (ii) the launch of particularly at the low dose of 10mg twice daily [93, three oral immunomodulatory drugs (�ngolimod, dimethyl 94]. fumarate, and teri�unomide), with more (e.g., laquinimod (ii) Nabiximols (Sativex) is a cannabis-based oral spray and �rategrast) in late stage development; (iii) a number of containing a de�ned quantity of speci�c canna- immunomodulatory monoclonal antibodies (alemtuzumab, binoids, particularly tetrahydrocannabinol and daclizumab,andocrelizumab)abouttoenterthemarket;and cannabidiol, which are cannabinoid CB1 and CB2 (iv)theemergenceofdrugstargetingsymptommanagement, receptoragonists,respectively[95,96].Sinceitactson including motor dysfunction (dalfampridine) and spasticity CNS neurons, BCNSB penetration is essential. 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