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REVIEWOpenAccessBlood-brainbarrierpermeabilityandphysicalexerciseMartaA.
Makiewicz1,2,ArkadiuszSzarmach3,AgnieszkaSabisz3,WiesawJ.
Cubaa2,EdytaSzurowska3andPaweJ.
Winklewski1,3,4*AbstractInthisnarrativereview,atheoreticalframeworkonthecrosstalkbetweenphysicalexerciseandblood-brainbarrier(BBB)permeabilityispresented.
WediscusstheinfluenceofphysicalactivityonthefactorsaffectingBBBpermeabilitysuchassystemicinflammation,thebrainrenin-angiotensinandnoradrenergicsystems,centralautonomicfunctionandthekynureninepathway.
ThepositiveroleofexerciseinmultiplesclerosisandAlzheimer'sdiseaseisdescribed.
Finally,thepotentialroleofconditioningaswellastheeffectofexerciseonBBBtightjunctionsisoutlined.
ThereisabodyofevidencethatregularphysicalexercisediminishesBBBpermeabilityasitreinforcesantioxidativecapacity,reducesoxidativestressandhasanti-inflammatoryeffects.
Itimprovesendothelialfunctionandmightincreasethedensityofbraincapillaries.
Thus,physicaltrainingcanbeemphasisedasacomponentofpreventionprogramsdevelopedforpatientstominimisetheriskoftheonsetofneuroinflammatorydiseasesaswellasanaugmentationofexistingtreatment.
Unfortunately,despiteasoundtheoreticalbackground,itremainsunclearastowhetherexercisetrainingiseffectiveinmodulatingBBBpermeabilityinseveralspecificdiseases.
Furtherresearchisneededastheimpactofexerciseisyettobefullyelucidated.
Keywords:Blood-brainbarrierpermeability,Physicalexercise,Inflammation,Brainrenin-angiotensinsystem,Centralautonomicfunction,KynureninepathwayIntroductionTheblood-brainbarrier(BBB)separatesthecentralner-voussystem(CNS)fromtheperipheraltissues.
InordertomaintainhomeostasisintheCNS,theBBBcontrolsmater-ial,nutrientsandcelltransferfromthebloodtothebrainandfromthebraintotheblood.
TheBBBrestrictstheentryofperipheralinflammatorymediators(e.
g.
cytokines,antibodies,etc.
),whichcanimpairneurotransmission[1].
TheBBBalsoparticipatesintheclearanceofcellularme-tabolitesandtoxinsfromthebraintotheblood[2,3]andregulatesthecompositionandvolumeofthecerebrospinalfluid.
TheBBBisacomplexstructureconsistingofendo-thelialcells,pericytes,vascularsmoothmusclecells,astro-cytes,microgliaandneurons[2,4–7]asislocatedbetweenthebrainparenchymaandthevascularsystem.
Interactionsbetweenthesecomponentshaveledtotheconceptoftheneurovascularunit,whereeachcelltypecontributestoBBBfunction[8].
ThemainstructuresresponsibleforthebarrierpropertiesoftheBBBaretightjunctions(TJs)[9–15].
Themaintenanceofadherence,gapandtightjunctionsbetweendifferentcelltypeswithintheneurovascularunitoftheBBBisessentialforCNShomeostasis[2,16].
BBBdistur-bancescommonlyoccurinneuronaldysfunction,neuroin-flammationandneurodegeneration[2].
NumerouspathologicstatescancausedisturbancesintheBBB,includingtrauma,hypoxia,infection,activationoftheclottingsystem,inflammation,dietarycomponents,en-vironmentaltoxinsandgeneticfactors[17].
Theassociationbetweenhigh-gradeinflammatoryresponsessuchasmen-ingitis,encephalitis,sepsis,localandsystemicinfectionsandincreasedpermeabilityoftheBBBformanysubstancesandimmunecellshasbeenwidelyacknowledged[18].
Re-cently,itbecameapparentthatlow-gradesystemicinflam-mationalsosubstantiallyaffectstheBBB[19].
Low-gradeinflammationaffectsabout40%ofthepopulationinWesterncountries,asitoccursduetometabolicsyndrome,insulinresistance,type2diabetes,arterialhypertension,*Correspondence:pawelwinklewski@wp.
pl1DepartmentofHumanPhysiology,FacultyofHealthSciences,MedicalUniversityofGdansk,TuwimaStr.
15,80-210Gdansk,Poland32-ndDepartmentofRadiology,FacultyofHealthSciences,MedicalUniversityofGdansk,Gdansk,PolandFulllistofauthorinformationisavailableattheendofthearticleTheAuthor(s).
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TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
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Makiewiczetal.
JournalofNeuroinflammation(2019)16:15https://doi.
org/10.
1186/s12974-019-1403-xdyslipidaemiaandobesity[20–22].
BBBdisruptionreferstoareductioninbarriertightnessandanincreaseinleakiness.
LossofBBBintegrityallowsfortheentranceofcytokinesandimmunecellsintotheCNS,whichactivatesglialcellsandcausesthealterationsintheextracellularenvironment.
Moreover,thesechangesleadtosecondaryinflammationandfurtherdamagetotheBBB,withtheleakageofplasmaproteinsandneurotoxicsubstances[23,24].
CNSinflammationdeterminestheseverityanddiseasecourseofnumerouspsychiatricandneurologicaldisor-dersandcanbebothcausedbyandresultfromBBBdysfunction;aninflammatoryresponseinthebrainmightleadtoendothelialcelldamageandincreasedBBBpermeability[25].
ThepermeabilityoftheBBBisalteredinmanyCNSpathologies,includingbraininjury,ische-micstroke,multiplesclerosis(MS),epilepsy,Parkinson'sdisease,Alzheimer'sdiseaseandmajordepression.
AconnectionhasalsobeenreportedbetweenBBBimpair-mentandpsychiatricdisorderssuchasmooddisorders,psychosis,autismspectrumdisorderandevenchronicsleepdisorder[1,26–29].
Ithasbeenwelldiscussedintheliteraturethatinflam-matorymechanismsarerelatedtothephysiopathologyofneuropsychiatricdisordersthroughseveralmechanisms.
Amongthemareglialactivation[30],neuronaldamageanddegeneration[31],increasedoxidativestress[32],re-ducedneurotrophicsupport[33],alteredneurotransmittermetabolism[34]andBBBdisruption[35].
Exercisetrainingisanimportantbehaviouralinterven-tionthathasnumerousbeneficialhealtheffects.
Epi-demiologicalstudiesindicatethatphysicalactivityleadstosystemicadaptationsandanelongatedhealth-span,thustimeoflifeingoodhealth,indifferenthumanco-horts[36,37].
Ampleevidencesuggeststhatthepracticeofphysicalexerciseimprovessomecardiovascularriskfactors,suchasthepercentageofbodyfat,insulinresist-anceandhighbloodpressure,whichareassociatedwithincreasedstiffeningofthearteries[38].
Moreover,ithasbeenshownthatphysicalexercisehasanimpactoninflammationandimprovedendothelialfunctionbyincreasingbloodflow,whichleadstoincreasedshearstress,stimulatingthereleaseofnitricoxide.
Inthisnarrativereview,weaimtoprovideastate-of-the-artsummaryoftheinfluenceofexerciseonBBBin-tegrity.
Consequently,wediscusstheinfluenceofphys-icalactivityonsystemicinflammation,thebrainrenin-angiotensinandnoradrenergicsystemsandcentralauto-nomicfunction,aswellasthekynureninepathway.
Therearenumerousmechanismsthroughwhichlong-termphysicalactivityaffectstheBBBandCNS.
Itcaneitherdiminishinflammationontheperipherallevel,therebyreducingtheriskofCNSinfiltrationofimmunecells,orprotecttheBBBthroughtheconstitutionofitstightjunctions.
ExerciseandsystemicinflammationDiabetesmellitusandobesityareexemplardiseasescharacterisedbylow-gradeinflammation[39,40].
Notably,inflammationandmetabolicdysfunctionarefrequentlyassociatedwithoxidativestressinadiposedepots[41–43].
Overweightandobesepatientswithadiagnosisoftype2diabetesmellitusshowincreasedbloodlevelsofpro-inflammatorycytokinesandmarkers(e.
g.
IL-1β,IL-6andTNF-α)[44–46].
Thesemoleculesarealsoincreasedinthebrain,cerebrospinalfluidandinthebloodofpa-tientswithAlzheimer'sdiseaseorothertypesofdementia[47];moreover,anoverlapbetweenthepathogenesisofAlzheimer'sdiseaseanddiabetesmellitusisevident.
Pro-inflammatorycytokinescanpassthroughtheBBBandinducestress-activatedpathways,promotingbrainin-sulinresistance,mitochondrialdysfunction[19]andtheaccumulationofneurotoxicbeta-amyloid(Aβ)oligomers[48]leadingtosynapticloss,neuronaldysfunctionandcelldeath.
Increasedceramideproductioncausedbydysregu-latedlipidmetabolismalsooccurswithinsulinresistance[49];thesemoleculescanpassthroughtheBBB,inducepro-inflammatoryreactionsanddisturbbraininsulinsignalling[50].
Physicaltrainingmaybecrucialinpreventingaswellasdiminishingthisdamage.
Regularphysicalexerciserein-forcesantioxidativecapacity,reducesoxidativestressandhasanti-inflammatoryeffects.
Itimprovesendothelialfunc-tionandmightincreasethedensityofbraincapillaries.
Physicaltrainingcanfurthercounteractdyslipidaemiaandreduceincreasedceramidelevels[51,52],anditmayhaveasuppressiveeffectontheBBBdamagecycle.
AbdEl-Kaderetal.
[53]presenteddatathatbothenduranceandstrengthtrainingcanpotentiallyalleviatetheinflammatorystateduetoareductioninTNF-αlevelsintype2diabetesmellituspatients.
DeSennaetal.
[54]havealsodemonstratedthatexerciseimprovesthestructuralcomponentsoftheBBBindiabeticrats.
Regularexercisetraininginducesareductioninadiposetissue-derivedpro-inflammatorycytokineslikeIL-6,TNF-αandMCP-1[55–58],whichareassociatedwithlow-gradesystemicinflammationandprovidesreductioninwhole-bodyinsulinresistance[59].
Importantly,physicalactivityisabletodecreaseinflam-mationindependentlyfromweightloss,throughareduc-tionininflammatorycytokinesreleasefromskeletalmuscles.
Similartoadiposetissueaswellasimmunecells,skeletalmuscle,whichisthelargestorganinthehumanbody,producesandreleasesinflammatorycytokinessuchasIL-4,IL-6,IL-8,IL-15andTNF-α[60–62].
Thesecyto-kinesarethereforealsocalledmyokines[60,63].
HandschinandSpiegelman[64]hypothesisedthatphysicalactivitycanbroadlysuppressmyokineexpressionthroughtheupregulationofskeletalmuscleperoxisomeproliferatoractivatedreceptor1α.
Theupregulationofthisreceptorisinducedbyphysicalactivity[65].
InastudybyAronsonetMakiewiczetal.
JournalofNeuroinflammation(2019)16:15Page2of16al.
[66],C-reactiveprotein(CRP)concentrationsdecreasedcontinuouslywithincreasinglevelsofphysicalfitness.
In-creasesincirculatingIL-6havebeenobservedafterper-formingexercisewithoutmuscledamage;thisinturnreducespro-inflammatorycytokinesviathestimulationoftheanti-inflammatorycytokinesIL-1raandIL-10[61].
ArecentstudybyChupeletal.
[67]showedthatphysicalexercisecanmaintainBBBintegrity.
Theanti-inflammatoryeffectofcombinedexercisetrainingandtaurinesupplemen-tationonperipheralmarkersofBBBintegrity,inflammationandcognitionin48elderlywomenwasinvestigated.
TheresultsshowedareductioninTNF-αandIL-6,aswellasareductionintheIL-1β/IL-1ra,IL-6/IL-10andTNF-α/IL-10ratiosinthecombinedexercisetraininggroup.
Inter-estingly,theimprovementincognitivefunctionwasreportedonlyinwomensubjectedtobothexerciseandtaurineaugmentation.
ExerciseandkynureninepathwayBrainandperipheralinflammatorystatescanalsopro-moteBBBfailurethroughtryptophan(TRP)catabolismasaconsequenceofkynureninepathwayactivation,whichisalsoconnectedwithglutamatergicexcitotoxicity.
Trypto-phanismetabolisedviaseveralpathways,themainonebeingthroughkynurenine(KYN)[68],whichisinvolvedinseveralconditionsincludingcancer,inflammatorydis-orders,diabetesmellitus,neurologicalandneurodegenera-tivediseases.
Tryptophanisdegradedintokynureninebytheenzymeindoleamine2,3-dioxygenase(IDO)[69,70].
Kynurenineisthenmetabolisedintoneuroprotectivekynurenicacid(KYNA)bykynurenineaminotransferases(KATs)orintoneurotoxicproductssuchasquinolinicacid(QUIN)oranthranilicacid.
QUINisaselectiveagon-istofN-methyl-D-aspartate(NMDA)receptors,andapo-tentneurotoxinduetoitsabilitytoinducetheproductionofreactiveoxygenspecies.
KYNreducestheactivityofnaturalkillercells,dendriticcellsorproliferatingTcells,whereasKYNApromotesmonocyteextravasationandcontrolscytokinerelease.
HighlevelsofQUINhavebeenassociatedwithneuronalexcitotoxicity,whereasKYNAhasbeenreportedasaneuroprotectivefactor[71]throughitsinhibitoryactionatglutamatergicexcitatorysynapses[72].
Amongthekynureninepathwaymetabolites,QUINislikelytobeoneofthemostimportantintermsofbio-logicalactivityandtoxicity[73].
BothKYNAandQUINhavebeenfoundtobedysregulatedinmajordepressivedisordersandschizophrenia[74].
Pro-inflammatorymedi-atorssuchasTNF-αcanpromoteQUINproduction[75],whileIL-1βpotentiatesquinolinate-mediatedexcitotoxi-city[68].
Thisisparticularlyimportantinsituationsin-volvingmacrophageinfiltrationacrosstheBBB.
InCNSinflammatorystates,IDOismainlyactivatedinmicroglialcells,whichpreferentiallymetabolisetryptophanintotheNMDAreceptoragonistQUIN.
ThemostpotentactivatorofIDOisinterferongamma(IFN-γ)[70,76].
Thereforeanimbalanceintype1/type2immuneresponses,associatedwithanastrocyte/microgliaimbalance,leadstoserotonergicdeficiencyandglutamatergicoverproduction.
Astrocytesarefurtherstronglyinvolvedinthere-uptakeandmetabolicconversionofglutamate.
Areducednumberofastrocytescouldcontributetobothdiminishedcounter-regulationofIDOactivityinmicrogliaandalteredglutamatergicneuro-transmission.
BindingofexcessglutamatetodysregulatedBBBendothelialcellionicNMDAreceptorsandmetab-otropicglutamatereceptorscanincreaseintracellularCa2+-dependentoxidativestressandBBBpermeabilitybyincreasingCa2+influxandreleasefromendoplasmicreticulumstores,respectively.
Skeletalmusclehasrecentlybeenadded[77]tothelistoftissuesthatcontributetokynureninepathwaymetab-olism.
Thishappensinthesettingofexercisetraining,whichenhancesKATgeneexpressionandtheconver-sionoftoxicKYNtoneuroprotectiveKYNA.
Theneuro-protectiveeffectofKYNAisgenerallyattributedtoitsantagonisticactiononNMDAreceptors.
IthasbeenfoundbyAndrásandcolleagues[78]thatahighglutamateleveldiminishesthefunctionoftheBBBviaendothelium-expressedNMDAreceptor-dependentoccludinphosphorylation.
KYNAisnotonlyanendogen-ousNMDAreceptorblockerbutalsoanon-competitiveinhibitoroftheα7-nicotinicacetylcholinereceptor[68,79,80];throughthismechanism,KYNAcandecreaseglu-tamaterelease[81].
Inthismanner,KYNAcanreducepathologicalglutamatelevelsandprotectthestructureoftheBBB[78].
TheeffectofexercisetrainingontheBBBhighlightsanimportantmechanismofinter-organcross-talkaskynurenineaccumulationcanbesuppressedbyactivatingitsclearanceinexercisedskeletalmuscles.
Exerciseandtherenin-angiotensin-aldosteronepathwayThereisalinkagebetweenangiotensinII(AngII),oneoftherenin-angiotensin-aldosteronefactors,andthedisrup-tionoftheBBB,especiallyinhypertensionstates[82–84].
AlthoughAngIIisknownasacardiovascularmediator,withaprimaryroleintheregulationofbloodpressureandfluidhomeostasis[85],itperformsasanimmunesys-temmodulatoraswell.
AngIIcaninitiateinflammationbyindirectpromotionofvascularpermeabilityandtherecruitmentofinflammatorycells[86].
AngIImayalsoactivatebothinnateandadaptiveimmunity[86,87].
AngIIdirectlymodulatestranscytoticandparacellularpermeabilityinBBBendothelialcellsandcouldcontrib-utetothepathophysiologyofhypertensiveencephalop-athy.
BothcirculatingAngIIviaAngIItype1receptors(AT1)ontheendotheliumandlocallysynthesisedAngIIcanresultinvasculardysfunctionandmicroglialactiva-tion,increasetheproductionofreactiveoxygenspecies,Makiewiczetal.
JournalofNeuroinflammation(2019)16:15Page3of16disruptendothelialnitricoxidesynthaseactivityandin-tensifypro-inflammatorycytokinesynthesis,whichareim-portantfactorsforsympathoexcitationcentressuchastheparaventricularnucleus(PVN)ofthehypothalamusandtherostralventrolateralmedulla(RVLM)inneurogenichypertension[88–90].
However,onestudyhasindicatedthatinhibitionofAT1blockshypertension-relatedincreasesincellpermeabilityandcerebraloedema,evenintheab-senceofloweredbloodpressure[91].
Thissuggestsarolefortherenin-angiotensin-aldosteronesystemandAngIIinmodulatingBBBfunction.
BBBdisruptionnotonlyfacili-tatesAngIIaccessbutalsoallowscirculatinginflammatorycellstoenterintothebrainparenchyma,contributingtofurthermicroglialactivationandinflammationinauto-nomicareassuchasthePVNofthehypothalamusandtheRVLM[89,90].
Theseresponsesalterneurovascularcoup-ling,dysregulatecerebralperfusionandmarkedlyaugmentneuronaldischarge,thusexacerbatingsympathoexcitationinhypertensiveanimals[83,92,93].
PhysicalexercisehasbeenshowntobehighlyefficientinreducingtheharmfuleffectofhypertensiononBBBleakageinautonomicbrainareas,whichstronglycorrelateswiththeimprovementofbothparasympatheticandsympatheticcontrolofcardiovascularparameters,eveninthepersist-enceofhypertension.
Recentstudieshaveestablishedtheefficacyofaerobictrainingtodownregulatethebrainrenin-angiotensinsystemandcorrectautonomicdysfunc-tioninspontaneouslyhypertensiverats[94,95].
Theserats,after2weeksofphysicalexercise,havebeenreportedtomaintainnormalangiotensinogenexpressionwithinauto-nomicareas,whichiscorrelatedwithreducedsympatheticoutflowtotheheartandvesselsandprecedesapartialfallinarterialpressure[96].
Exercisetrainingrestoresthebal-ancebetweentheexcitatoryandinhibitoryneurotransmit-tersaswellasbetweenpro-andanti-inflammatorycytokines,andattenuatesoxidativestressinthePVN[97].
Trainedspontaneouslyhypertensiveratsdemonstrateaninstantnormalisationofthebaroreceptorreflexcontrolofheartratethatcoincideswithamarkedreductioninoxida-tivestressandinflammationinthehypothalamicPVN[98].
Similartraining-inducedeffectshavealsobeenobservedinotherautonomicareas[94,95].
Itisalreadyknownthatacutephysicalactivityinducessympatheticmodulation[99].
Conversely,regularexercisemaybeassociatedwithprogressivesympatheticwithdrawalandincreasingpara-sympatheticdominanceasaresultofadaptationsoftheperipheralandcentralregulatorysystems[99].
Ithasbeenshownthathypertensionischaracterisedbyautonomicim-pairment,BBBleakageandAngII-inducedneuronalactiva-tionandthatexercisetrainingishighlyeffectiveatpreventingAngII-inducedeffectsandimprovingauto-nomicfunction[100].
PhysicaltrainingchangesthetissueAngIIcontentaswellandsuppressesmicroglialactivation,crucialfactorsforboththemaintenanceofBBBintegrityandthenormalisationofautonomiccontrolofthecircula-tioninhypertensiveindividuals.
Accordingtosomeau-thors,theremaybeasystemofglobalcontroloverthepermeabilityofthecerebralmicrovasculatureviathecho-linergicnervoussystem[101].
Duetothefactthatexerciseinducesashifttowardparasympatheticdominance,thismechanismmayalsobefavoured.
Thereisaninteractionbetweenneurotransmitters,pro-inflammatorycytokinesandenhancedoxidativestressinthePVNwhichplayakeyroleinsympatheticregulationofbloodpressure[95].
Inspontaneouslyhypertensiverats,reactiveoxygenspeciesintheRVLMareknowntoenhanceglutamatergicexcitatoryinputsandimpairGABAergicin-hibitoryinputstotheRVLM,resultinginincreasedsym-pathoexcitatoryinputtotheRVLMfromthePVN[102].
Amongtheknownpressoragents,AngIIandglutamateplaypivotalrolesinthebraincentresinvolvedinbloodpressurecontrolinbothnormotensiveandspontaneouslyhypertensiverats[103].
Thelinkbetweenbrainangiotensi-nergicandglutamatergicsignallinghasbeendemonstratedbyVieiraetal.
[104].
Themajorsympatheticoutputpath-wayforthetonicandreflexcontrolofbloodpressure,whichusesglutamateasatransmitter,arisesintheRVLM[105].
InjectionofAngIIintotheRVLMofunanaesthe-tisedratsexaggeratesthepressorresponsetoglutamate.
Additionally,ithasbeenspeculatedthatAngIItakespartinglutamatepressorresponsesviaapresynapticincreaseinglutamatergicinputintotheRVLM[106].
Referringtothis,KYNA(aglutamateantagonist)isthoughttobeahypotensiveagent.
Millsetal.
[107]havereportedthatintrathecalKYNAadministrationdecreasesbloodpressure,especiallyinanesthetisedspontaneouslyhypertensiveratsandstroke-pronespontaneouslyhypertensiverats,withalessnoticeableeffectinnormotensiverats.
Itcanbeassumedthatinhypertensionstates,thereisanabilityofphysicalexercisetocorrectsympathetichyperactivity,reduceAngIIavailability,decreaseoxida-tivestressandinflammationinthePVNandRVLMandrestoreBBBintegrity.
ExerciseandbrainnoradrenergicsystemDuringphysicalexercise,itiswellknownthatperipher-allycirculatingepinephrineandnorepinephrine(NE)ac-tivateβ-adrenoceptorsofthevagusnerveafferentsprojectingtothelocuscoeruleus,whichplaysapivotalroleintheregulationofautonomicactivityandcognitivefunctions[108–112].
Theoptimalstimulationoflocuscoeruleusmightbeacrucialelementofmodulatingcog-nitivefunctionwithexercise[113].
BrainNEisalsore-portedtosuppresstheinflammatorygenetranscription.
ItisclearfromthefindingsofHetieretal.
[114]andFrohmanetal.
[115]thatanti-inflammatoryactionofNEisexertedviamicrogliaandastrocytesβ2-receptors.
Immunecellsexpressbothtypesofreceptors,andTandMakiewiczetal.
JournalofNeuroinflammation(2019)16:15Page4of16Blymphocytesexpressβ2-receptorsalmostexclusively[116].
Engagementofβ2-receptorsactivatesacascadeofsignalingintermediates,includingcyclicadenosinemonophosphate(cAMP)andproteinkinaseA,whichleadstothephosphorylationofcellularproteins[116].
NEalsopro-motesashiftofTh1/Th2balancetowardTh2responsebyactivatingβ2-receptor[117].
Otheranti-inflammatoryef-fectsofNEhavealsobeenreported,includingthesuppres-sionofinduciblenitricoxidesynthase,interleukin-1b,tumornecrosisfactorαandintercellularadhesionmolecule-1.
AttentionisalsodevotedtothefactthatNEenhancesbrain-derivedneurotrophicfactorproduction,whichplaysanimportantroleinneuronalsurvival,neuro-plasticityandneurogenesis[37,118].
Thisinteractionofbrain-derivedneurotrophicfactorismediatedbyβ1/β2,andα2-adrenergicreceptorsandsharessimilarcellularpathwayswithanti-inflammatoryNEaction[118–120].
Neuronsmetabolizeglucoseprimarilyinthepentosephosphatepathwayinordertoproduceadenosinetriphos-phate(ATP)tosupportbrainfunctions,includingglutathi-oneregeneration,whichprotectstheneuronfromreactiveoxygenspecies(Bélangeretal.
2011),andconsequentlystandsforproperBBBfunctioning.
Apartfromusingglu-coseasthefirstchoice,lactateisalsousedbythebrainasafuelforneurons[121,122].
Thisprocessoccursintheas-trocytes,wheretherecruitmentofenergyfromtheirglyco-genstores[123]isfacilitatedbynoradrenergicstimulationoftheastrocytes'β-adrenoceptorssignalingthemtoconvertglycogentolactate[124,125],whichisthentransportedtotheneurons[126].
Inresponsetophysicalexercise,thelactateproductionbyskeletalmusclesincreases[127,128],asdoestheexpressionofthelactatetransportermonocar-boxylatetransporter1attheBBB[129–131].
Lactatepro-ducedduringexerciseisalsoreportedtoincreaselevelsofgrowthfactorsimportanttoangiogenesis,neurogenesis,calciumsignaling,axonalmyelination,synapticplasticityandmemoryformation[132–134].
Energeticinsufficiencyinneuronsduetoinadequatelactatesupplyisimplicatedinseveralneuropathologies,includingattention-deficit/hyper-activitydisorder[135–137].
ExerciseinmultiplesclerosisMShasrecentlyattractedtheinterestofnumerousre-searchers[138]regardingtheapplicationofphysicalactiv-ity.
InMS,thereisanextrinsicBBBdisruptionpatternwiththeinitialinjuryinthebloodvessels,allowingTandBcellstocrosstheBBB[139]withtheexudationoffibrin,whichcausesaninflammatoryreactionleadingtodemyelination[140],immunecellinfiltrationandaxonaldamage.
Inac-cordancewithastudybyMokhtarzadeetal.
[141],ithasbeenshownthat8weeksofexercisetrainingnormalisestheconcentrationofparticularBBBpermeabilitymarkersinMSpatients,includingS100calcium-bindingproteinB(S100B).
Additionally,accordingtoWhiteetal.
[142],exerciseispotentiallyabletocounteracttheimbalancebe-tweenthepro-inflammatoryTh1cytokinesandtheanti-inflammatorycytokines(forexampleIL-10)byenhan-cinganti-inflammatorymechanismsinMSpatients.
AccordingtoRossietal.
[143],exercisecanprotectfrominflammation-inducedneurodegenerativesynapticanddendriticalterationsintheexperimentalauto-immuneencephalomyelitismousemodelofMS.
Inthisstudy,exercisehasbeenshowntoincreasesynapticdensityandgrowthinthehippocampus[143].
InanimalmodelofMS,positiveeffectsofexerciseuponcognitionarealsoreported[144,145].
Moreover,anincreaseinneurotrophins[145]andbrain-derivedneurotrophicfac-tor[146]inresponsetoexercisehasbeenfound.
However,thereisstillanurgeforhumanresearches.
TheanalysesofstudiesindicatethatideallybothaerobicandresistanceexercisesmaybenefitpersonswithMS.
Asubstantialincreaseinhippocampalvolumehasbeenre-portedinMSsubjectsrandomizedtoanaerobicexerciseprogramcomparedwithanonaerobic-trainedcontrol[147].
PhysicalfitnessexercisecorrelateswithimprovedcognitivefunctioninpersonswithMS[148,149].
AnotherfindingindicatesthatcardiorespiratoryfitnessinpatientswithMSpredictsneuronalplasticity[150]andincreasedgraymattervolume,betterwhitematterintegrityandim-provedperformanceontestofinformationprocessingspeed[151].
ThereissomeevidenceforneuroprotectiveeffectsofexerciseinhumanswithMS,comparingaerobictoaerobicplusresistanceexercisetrainingresultingindecreasesinanti-inflammatorycytokines[148].
Basedonthesefindings,itcanbepostulatedthatphys-icalexercisereducesinflammationand,asaconsequence,BBBimpairment,andthushasaprotectiveeffectonCNSinMSpatients.
IfphysicalactivityisabletoenhanceBBBstabilityintheseparticularpatients,wecanpredictthatitwillimproveBBBfunctioningeneral.
Nevertheless,studieswithlargergroupofpatientsandclearlydevelopedexerciseprotocolsareneededtoincludephysicalactivitysessionsasastandardofcaretherapeuticprocedures.
ExerciseinAlzheimer'sdiseaseInAlzheimer'sdisease,theintegrityofBBBmaybedisor-deredaccordingtoaccumulationofreactiveoxygenspeciesactivatingmetalloproteinaseswhichleadstobreakdownofBBBthroughdestructionofbasementmembraneandtightjunctions[152],aswellasduetotheaccumulationofchol-esterolmetabolism[152],andimpairedinsulinsignaling[153].
IntheprevalenceofBBBmaintenancecomplications,theamplifiedAβmicrovesselsdepositsprocessbegins.
AsAβfibrilsaccumulate,itresultsinacascadeofsignificantbraindegenerationandatrophyofhippocampalandcor-ticalstructures.
BBBdysfunctionduringAlzheimer'sdiseaseinfluencesAβclearanceandendothelialtransport,impairsMakiewiczetal.
JournalofNeuroinflammation(2019)16:15Page5of16endothelialcellandpericytefunctions,affectsTJintegrity,activatesglialcellsandfacilitatestherecruitmentofleuko-cytesinthebrain[154–158].
PhysicalactivitycanimproveAβclearancebyupregu-latingAβtransportersandreducetheaccumulationofAβpeptidesinthebrainparenchymabyacceleratinginterstitialfluiddrainage,whichdiminishesneuroinflam-mation[159].
AlthoughadirecteffectonspecificAlzhei-mer'sdiseasepathologyisstillunproven[160],oneresearchdocumentedareductionintauincerebrospinalfluidasaresultofexerciseinolderadultswithmildcog-nitiveimpairment[161].
Exercise,primarilyaerobic,im-provescognitivefunctioninseveralpatientpopulations,includingAlzheimer'sdisease,elderlypeopleatriskforcognitiveimpairmentandhealthyolderadults[162,163].
Inaddition,bothanimalandhumansstudiessug-gestthatphysicalactivitymayhavearoleinmodifyingthediseaseprocessandmaintainingcognitivefunctioninAlzheimer'sdisease[11].
Physicalactivityinterven-tionshasapositiveoveralleffectoncognitivefunction,andtheeffectisdrivenbyinterventionsthatincludedaerobicexercisesindependentofthetypeofdementia[164],whichhasbeenrecentlyprovedinmeta-analysisconductedbyhmanetal.
[165].
Furtherstudiesshallunveilif/howneuroinflammationandBBBdysfunctionarerelatedtocognitivefunctionimpairmentandoverallAlzheimer'sdiseaseprogression.
Then,specificphysicalactivityprotocolsmaybedevel-opedtosupportpatientscare.
Exercise-inducedconditioningPhysicalactivityacutelyelevatesthereleaseofadrenaline,cortisol,growthhormone,prolactinandotherfactorswithimmunomodulatoryeffects[166].
Consequently,veryhighintensityexercisecantriggersystemicinflammation,asub-sequentimmunodepressionandthusahigherriskofinfec-tions[167].
AccordingtoRohetal.
[168],moderate-and/orhigh-intensityexercisemayinducehigheroxidative-nitrosativestressthanlow-intensityexercise.
Whileacuteintenseexerciseprovokesaspikeintheactivityofinflammatorycells(likeleukocytes)andplasmaCRPconcentrations,repeatedboutsofsubmaxi-malintensityexerciseinduceadaptivemechanismsthatcancounteractinflammationinthelongterm[169].
Thesechangesaremeasurableasreductioninthecon-centrationofinflammatorymediatorssuchasCRP,IL-6andTNF-α,whileenhancingtheproductionsoftheanti-inflammatoryIL-10[170].
Therearesomecontrastingstudiesregardingthein-fluenceofphysicalexerciseonBBBintegrity.
S100BisconsideredtobethebestindicatorofBBBpermeability[168,171,172]andcanevenpredicttheseverityofbraininjury[168,173].
ElevatedS100Blevelshavebeenre-cordedfollowingexerciseandaremostlyattributedtoeitheranelevationinBBBpermeabilityorheadtrauma[174–176].
IncreasedserumconcentrationsofS100BhavethereforebeenusedtoassociateCNSpathologywithBBBdysfunction.
However,evenintheabsenceofheadtrauma,itappearsthattheBBBmaybecompro-misedfollowingexercise,withtheseveritydependentonexerciseintensity.
AccordingtoSharmaetal.
[177],short-termforcedswimmingexerciseincreasestheper-meabilityoftheBBBinspecificbrainregionsinrats,likelymediatedthroughserotoninvia5-HT2receptors.
IntenseexercisehasthepotentialtoincreaseS100BandinduceBBBfunctionaldeteriorationwithoutcausingstructuralbraindamagesubsequenttoafreeradical-me-diatedimpairmentindynamiccerebralautoregulation[178].
Afteracuteexercise,highlevelsofmyokinesaresecretedbytheskeletalmuscle,exertingavarietyofendocrineeffects.
Theinductionofmyokineslikemyostatin,IL-7,decorinandleukaemiainhibitoryfactorisinvolvedintheregulationofmusclehypertrophyandmayplayaroleintherestructuringofskeletalmuscleasaresponsetoexer-cise[179].
ExercisereducestheexpressionofToll-likereceptorsatthesurfaceofmonocytes;thesereceptorshavebeenimpli-catedasmediatorsofsystemicinflammation[180].
Musclefunction,inflammationandexercisearehenceintrinsicallylinkedinacomplexmanner[64,181].
Theinductionofthebeneficialversusdetrimentaleffectsofphysicalactivitythereforeseemstobehighlycontext-specific.
Forexample,IL-6wasoriginallyclassifiedasaprototypicalpro-inflam-matorycytokine,althoughanti-inflammatorypropertieshavealsobeendescribed[182].
SomestudieshaveprovideddatashowinganincreaseinIL-6concentrationsdirectlyafterphysicalactivity,suggestingthatIL-6wasreleasedfromthemusclemassandactsasamyokine,ratherthanatypicalpro-inflammatorycytokine[183].
BesidestheproductionofIL-6inactivatedimmunecells,thesystemicelevationofIL-6inpatientswithmetabolicdiseaseshasstrengthenedthelinkbetweenIL-6andinflammation.
Instarkcontrast,however,exercise-inducedelevationsinIL-6plasmalevelsleadtoincreasedcirculatinglevelsofseveralpotentanti-inflammatorycytokinessuchasIL-1raandIL-10,andalsoinhibitTNF-αproduction,suggestingthatIL-6mayalsohaveanti-inflammatoryproperties[184,185].
SkeletalmusclefibresalsoexpressandreleaseIL-6duringandafterexercise[186–189].
IL-6productionislikewiseboostedinconnectivetissue,thebrainandadiposetissuepost-exercise[60].
Thus,inthecaseofexercise,IL-6exertsanti-inflamma-toryeffects[63].
Thismechanismmayexplainwhylowerbaselinelevelsofpro-inflammatorycytokinesarepresentinthosepeoplewhoaremostphysicallyactive[190].
Cellsre-spondtothestressfulstimulusofexercisebyactivatingpathwaystoabolishit;inthiscase,byincreasingtheMakiewiczetal.
JournalofNeuroinflammation(2019)16:15Page6of16expressionofenzymessuchassuperoxidedismutaseandglutathioneperoxidaseorbyincreasinglevelsofanti-oxidativeperoxiredoxins.
Alikelymediatorofthisre-sponseareproteinsrelatedtotheNFκBpathway,whichcanactivatethegeneexpressionofanti-oxidativeproteinsandshowenhancedDNAbindingaround2hafteracuteexercise[191,192].
Consequently,physicalactivityreducestheproductionofreactiveoxygenspeciesandenhancestheanti-oxidativedefence[193,194].
Inskeletalmuscleinparticular,repeatedmoderateintensityexerciseimprovestheanti-oxidativecapacitybyupregulatingendogenousanti-oxidativemolecules[195,196].
Thus,wecanassumethatbrief,intensephysicalactivityincreasesthepermeabilityoftheBBB[177]andinducesinflammation,butlong-termregularexercisemayhaveaprotectiveroleonBBBintegrityandactivateanti-inflam-matorypathways.
PhysicalExerciseandBBBtightjunctionsTheBBBiscomposedofendothelialcellsformingase-lectivevascularnetworkthroughtheexpressionoftightjunction(TJs)complexes,whicharedefinedasmole-culesthatinteractintheextracellularjunctionalspaceorasmoleculesthatactasanchorswithintheendothe-lialcelltocreatetheBBB[174].
Tightjunctionsbetweenbrainendothelialcellsareconstitutedbythreemajortransmembraneproteins:occludin,claudinsandjunctionassociatedmolecules,aswellasseveralcytoplasmicpro-teinsincludingzonulaoccludens[197].
BrainendothelialTJsexpressclaudin-3and-5andpossiblyclaudin-12[198,199].
Claudin-5hasbeenshowntoactivelycon-tributetoBBBintegrity[200].
Manystudieshaveindi-catedthatoccludin,claudin-3andclaudin-5areinvolvedinBBBgenesis[199,201]andthecontrolofparacellularpermeability[202–205].
TJscanberegulatedbytheactivationofvariousrecep-torsofvasoactivecompounds(bradykininandAngII)aswellasadhesionmoleculesorreactiveoxygenspecies.
Intercellularadhesionmolecule1(ICAM-1),vascularcelladhesionmolecule1(VCAM-1)andplateletandendothe-lialcelladhesionmolecule1(PECAM-1),membersoftheimmunoglobulinsuperfamily,activelycontributetothefirmadhesionand/ormigrationofleukocytesintotheCNSthroughthecytokine-activatedbrainendothelium[206,207].
Agentsreleasedfrommostofthecellsoftheneurovascularunitduringpathologycanmodulatebrainendothelialtightjunctions,withseveralinflammatoryme-diatorsexacerbatingBBBpermeability;onlyafewagentsareabletocounterorreversethiscourse[1].
Thepro-longedpresenceofoxidative/inflammatoryfactorscanre-sultinchangestoorthelossoftightjunctionsandintegrins(e.
g.
β1,αvandα6integrins),leadingtosenes-cenceanddetachment-mediatedcelldeath[23,208].
ItisknownthatbothIFN-γandTNF-αcanalterBBBpermeabilitybyaffectingthecellulardistributionofjunc-tionaladhesionmoleculesandbycrucialupregulatingtheexpressionofICAM-1andVCAM-1[209–211].
ChangesinBBBpermeabilityareconnectedwithalter-ationsinoccludinexpression[212]andendothelialbarrierfunction[202].
Theselectivityofclaudin-5expressioninbrainendothelialcellssuggeststhatitisessentialforBBBfunction[213],asithasbeendemonstratedthatclaudin-5participatesinmodulatingpermeabilitytoionsaswellasmacromolecules[214].
SeveralstudieshaveindicatedthatalteredpermeabilityoftheBBBisaccompaniedbydecreasedclaudin-5expression[213].
AttentionshouldbealsodevotedtorecentresearchbySouzaetal.
[215]regardingtheimpactofphysicalexer-cise,whichre-establishestheexpressionofTJproteinssuchasoccludinandclaudin-4intheCNStobasallevelsandinhibitstheexpressionofPECAM-1.
Thisstudywasbasedonexperimentalautoimmuneenceph-alomyelitis,amousemodelofMS.
ThestudysuggeststhatphysicalexercisemaintainstheintegrityoftheBBBbypreservingtightjunctions.
Additionally,Schreibeltetal.
[216]demonstratedthatphysicalexerciseinMSpre-servesthelevelsofclaudin-4andoccludininthespinalcordofmice,byinhibitingtheproductionofreactiveoxygenspeciesandtheinductionofoxidativestress.
Moreover,somestudieshaveprovideddatathatinhibit-ingglycogensynthasekinase-3βpromotesTJstabilityinbrainendothelialcellsbyextendingthehalf-lifeofocclu-dinandclaudin-5andincreasingtheirlevels,whichdoesnotinvolvetheirgeneregulation[217].
AstudybyIslaetal.
[218]showedafavourableeffectofvoluntaryexer-ciseinvolvingareductioninglycogensynthasekinase-3βrecruitment,resultinginprotectionoftheBBBthroughTJs.
Theinhibitionofglycogensynthasekinase-3βhasalsoanti-inflammatoryeffectonbrainendothelialcells[219].
Inadditiontothebarrier-enhancingroleofglycogensynthasekinase-3βinhibitors,itgivesapromisetotheirutilityinrepairandprotectionoftheBBB.
ClinicalsignificanceofexerciseHumanorganism'sresponsetorepeatedhighlevelsofphysicalexerciseprovidesanintegrationofcells,organsandorgansystemsinordertominimizehomeostaticdisruptionsduringandafterexercise,whichisastressstimuli.
Regularmoderate–highlevelsofexercisemaybeperceivedasphysiologicalasduetothesedentarylife-style,thereductionofthemaximalcapacityoforgansystemsisobserved,leadingtoseveralpathologicalpro-cesses.
Therefore,individualswithhighlevelsofexercisecapacitypresentdecreasedprevalenceofpathologicalchronicdiseasesandofmortality[36].
Physicalinactivityisaprimarycauseofseveralchronicdiseases[220].
Physicalexerciseimprovescerebrovascular,Makiewiczetal.
JournalofNeuroinflammation(2019)16:15Page7of16metabolicandendothelialfunction,whichreducesoxida-tivestressandneuroinflammation,contributingtoim-provedneuronalfunction[221–223].
Moreover,exerciseisassociatedwithincreasesinlevelsofbrain-derivedneu-rothropicfactorandinsulin-likegrowthfactor1[160,223,224].
Theaccumulatingevidencereinforcesthepositionthatregularaerobic[225,226]and,withlessevidenceofeffectiveness,resistancetraining[227]offerapowerfultooltocopewithbiologicagingofselectedcentralner-voussystemfunctions.
Figure1depictstheconvergenceofmultiplepathways,activatedbyexercise,onafinal,anti-inflammatorycommonpathway.
Inthegeneralpopulation,exerciseimprovesattention,processingspeed,memoryandexecutivefunctioning.
Exercisealsoincreaseshippocampalvolumeandwhitematterintegrityinhealthyolderadults[228,229].
Itisabehavioralinterventionthatshowsgreatpromiseinalle-viatingsymptomsofsomementaldisorderssuchasde-pression[230]andcansignificantlyimprovepositivesymptoms,negativesymptomsandsocialfunctioninginpatientswithschizophrenia[231–233].
ApartfromplayingaroleindiminishingthediseasesassociatedwithleakyBBB,physicalexerciseisknowntoinducebeneficialeffectsindifferentsystems,e.
g.
thecardiovascular,muscular,metabolic,neural,respiratoryandthermoregulatory[234–238].
Physicaltrainingresultsinanincreaseintheconcentrationoftheanti-inflammatorycytokineIL-10andadecreaseinthepro-inflammatorycy-tokinesIL-1βandTNF-α[239].
Exercisetraininghasalsobeenreportedtoamelioratetheinflammatoryprofileinpatientsafteramyocardialinfarctionbyenhancingtheexpressionoftheanti-inflammatorycytokineIL-10[240].
AccordingtoLinetal.
[241],IL-10improvespropertiesoftheBBBinaratmodelofsevereacutepancreatitisbyattenuatingthedownregulationofclaudin-5expressionandtheimpairmentoftightjunctionsandbyanti-apop-toticeffectsonbrainmicrovascularendothelialcells.
Harrisetal.
[242]haveshownthatexercisemodulatesimmunologicalandexertsanti-inflammatoryeffectsintheCNS,suchthatdepression-likesymptomsarereduced.
Moreover,exercisereducestheexpressionofToll-likere-ceptorsonthesurfaceofmonocytes[180,243–245],whichmayrepresentabeneficialeffectasToll-likereceptorsareresponsibleformediatingthecapacityofmonocytesandmacrophagestoproduceinflammation[246–248].
Theaccumulatingevidencereinforcesthepositionthatregularaerobic,andpossiblyalsoresistancetraining,playsanimportantroleinmaintenanceofhealthyFig.
1Alow-gradesystemicinflammationobservedinmetabolicsyndrome,insulinresistance,type2diabetes,arterialhypertension,dyslipidaemiaandobesitycontributestoBBBdamageviapro-inflammatorycytokinesinducingkynureninepathwayleadingtoneurotoxicprocessonBBBanditspermeability.
Ininflammatorystates,ROSarealsoproducedandmayimpairTJsstructureandfunctioncausingthedirectdamageofBBB.
RAAsystemactivationduetothesystemicinflammationincreasesthedestructionofTJsandproductionofROSleadingtofurtherdamageofTJsandBBB.
Physicalexercisecounteractsobesityanddiminishesthelow-gradesystemicinflammation,productionofROSandchangeskynureninepathwaymetabolismcourseintoneuroprotectiveagentsaswellasdownregulatesbrainRAAsystem,whichallleadstoBBBprotection.
BBBblood-brainbarrier,ROSreactiveoxygenspecies,TJstightjunctions,RAArenin-angiotensin-aldosteroneMakiewiczetal.
JournalofNeuroinflammation(2019)16:15Page8of16structuresandfunctionsofthehumanbody[37].
Beingavaluablecomponentintheclinicalmanagementofavarietyofdiseases,itisrecommendedforthesepurposesinnumerousevidence-basedclinicalguidelines[249,250].
Thereisacurrentneedofnovelnonpharmacologi-calstrategiessuchasphysicalexercisethatcanprovidevaluableadjunctivetreatmentbutfurtherstudiesarewarrantedtodeciphertheexactrolephysicalexerciseplayinsomeneuroinflammatorydiseases.
ConclusionsandfuturedirectionsInthisreview,atheoreticalframeworkonthecrosstalkbetweenphysicalexerciseandBBBpermeabilityispre-sented.
Inourmodel,physicalexerciseinfluencestheBBBthroughanumberofanti-inflammatoryeffectsandleadstoareductioninlesionsandvascularpermeability(Fig.
1).
BBBbreakdowngenerallyculminatesinneuronaldysfunction,neuroinflammationandneurodegeneration.
Thepathogenesisofnumerousdiseaseshasbeenrecentlyshowntobeinflammatoryinnature,andthereisincreas-inginterestinnon-pharmacological,alternativemethodsoftreatment.
RegularphysicalexercisediminishesBBBpermeabilityasitreinforcesanti-oxidativecapacity,reducesoxidativestressandhasanti-inflammatoryeffects.
Itimprovesendothelialfunctionandmightincreasethedensityofbraincapillaries(Fig.
2).
Althoughphysicalexercisehaspositiveeffectsonbrainfunction,therehavebeenonlyafewstudiesasses-singthelong-termconsequencesofphysicalactivityonBBBpermeability.
Toourknowledge,thereareonlytwostudiesthathavedirectlyexploredthenexusbetweenregularexerciseandBBBparameters.
Mokhtarzadeandcolleagues[141]indicatedanimprovementinBBBleak-agemarkers,includingS100B,after8weeksofexerciseFig.
2Insystemiclow-gradeinflammatorystates,cytokinescanstimulateROSproductiondestroyingtightjunctionsandincreasingBBBpermeability.
CytokinescanalsoactivateIDOcatalyzingdegradationoftryptophanintoKYN.
KYNcanbetransformedintoneuroprotectiveKYNAbyKATsenzymeorintoneurotoxicproducts,mainlyQUIN,whichstimulatesNMDAreceptorsandleadstoglutamatergicoverproductionincreasingCa2+influxandBBBbreakage.
Low-gradeinflammationininsulinresistancecauseslipiddysregulationandincreasedceramideproductionanditspassthroughtheBBB,intensifyingbraininflammationandpromotingAβproduction.
InleakystatesofBBB,TJslosetheirfunctionandpro-inflammatoryfactorscaneasilypassthroughBBBleadingtoitsfurtherdamage.
Thepresenceofinflammationandincreasedoxidativestressinbrainimpairsignificantlymitochondrialandneuronalfunctionscausingcelldeath.
DuringBBBdisruption,facilitatedAngIIaccesscaninitiateinflammationbypromotionofvascularpermeabilityviaAT1receptors,risingtherecruitmentofinflammatorycells,ROSproduction,microglialactivationandinflammationinautonomicareassuchasthePVNandtheRVLM,whichpotentiateglutamatergictoxicity.
PhysicalactivityenhancesKATgeneexpressionandtheconversionoftoxicKYNtoneuroprotectiveKYNA,whichprotectsBBB.
Duringphysicalactivity,themusclesreleaseofanti-inflammatorycytokinesIL-1raandIL-10,whichcanitselfreducetheconcentrationofpro-inflammatorycytokines(TNF-α,IL-1,IL-6,IL-17)aswellasbyupregulationofskeletalmuscleperoxisomeproliferatoractivatedreceptor1α.
NEreleasedduringphysicalactivityactsviamicrogliaandastrocytesβ2-receptorsandlymphocytesβ2-receptorsreducingtheneuroinflammation.
PhysicaltrainingalsodiminishesthetissueAngIIcontentandcansuppressmicroglialactivationinthePVNandtheRVLM.
Physicalexercisereinforcesantioxidativecapacitybyupregulatingendogenousanti-oxidativemolecules,reducesoxidativestressandceramidelevelswithasuppressiveeffectontheTJsandBBBdamagecycle.
AngIIangiotensinII,AT1angiotensinIItype1,BBBblood-brainbarrier,IDOindoleamine2,3-dioxygenase,KYNkynurenine,KYNAkynurenicacid,KATskynurenineaminotransferases,NEnorepinephrine,NMDAN-methyl-D-aspartate,PVNparaventricularnucleus,QUINquinolinicacid,RVLMrostralventrolateralmedulla,ROSreactiveoxygenspecies,TJstightjunctions,TRPtryptophanMakiewiczetal.
JournalofNeuroinflammation(2019)16:15Page9of16traininginMSpatients.
Souzaandcolleagues[215]demonstratedintheexperimentalautoimmuneenceph-alomyelitismousemodelthata4-week-longexerciseprogramresultedinimmunomodulatoryandantioxidanteffectsaswellasinthemaintenanceofBBBintegritybypreservingitstightjunctions.
Consequently,despitesoundtheoreticalbackground,itremainssofarunclearastowhetherexercisetrainingiseffectiveinmodulatingBBBpermeabilityinspecificdiseases.
Inparticular,thepotentialmagnitudeofBBBfunctionimprovementorrestrainofdisease-relatedBBBdeteriorationhastobeinvestigated.
Moreover,theinfluenceofdifferentkindsexerciseandthequantityofphysicalactivityrequiredtoinducemeaningfulresponsesremaintobeclarified.
Novelimagingmodalitiesareavailabletostudydisrup-tionoftheBBBinhumansstartingfromlargeperme-abilityleaksobservedinMStomoresubtlechangesinchronicvasculardiseaseanddementia[251].
Conse-quently,futurestudiesshouldlinkBBBpermeabilitywithclinicalpresentationofthepatients.
Moreover,fur-therresearchisrequiredtodeterminethesignificanceofBBBprotectionwithphysicalexerciseinrelationtofunctionalbenefitsforpatientssuchasimprovedcogni-tionanddailyfunctioning.
Finally,theeffectsofexerciseoninteractionsbetweenneuroinflammatorystatusandBBBpermeabilityshallbedefinedinexperimentalstudies.
TherapeuticinterventionstargetingdisturbancesinBBBfunctionmightthereforehaveapromisingeffectinabroadspectrumofdisorders.
Physicaltrainingcanbeemphasisedasacomponentofpreventionprogramsdevelopedforpatientstominimisetheriskoftheonsetofinflammatorydiseasesaswelltocomplementtreat-ment.
MoreresearchisneededastheimpactofexerciseonBBBfunctionisyettobefullyelucidated.
AbbreviationsAngII:AngiotensinII;AT1:AngiotensinIItype1;ATP:Adenosinetriphosphate;Aβ:Beta-amyloid;BBB:Blood-brainbarrier;cAMP:Cyclicadenosinemonophosphate;CNS:Centralnervoussystem;CRP:C-reactiveprotein;ICAM-1:Intercellularadhesionmolecule1;IDO:Indoleamine2,3-dioxygenase;IFN-γ:Interferongamma;KATs:Kynurenineaminotransferases;KYN:Kynurenine;KYNA:Kynurenicacid;MS:Multiplesclerosis;NE:Norepinephrine;NMDA:N-methyl-D-aspartate;PECAM-1:Plateletandendothelialcelladhesionmolecule1;PVN:Paraventricularnucleus;QUIN:Quinolinicacid;RVLM:Rostralventrolateralmedulla;S100B:S100calcium-bindingproteinB;TJs:Tightjunctions;TRP:Tryptophan;VCAM-1:Vascularcelladhesionmolecule1AcknowledgmentWewouldliketothankAgataMajewskafortheexcellenttechnicalsupport,includingpreparationofFigures1and2.
WewouldliketothankSzymonM.
Zdanowskiforsupportintextediting.
FundingDoctorsArkadiuszSzarmachandPawelJ.
WinklewskiaresupportedbythePolishNationalScienceCentre(NCN)grantsnumbers2017/01/X/NZ4/00779and2017/01/X/NZ5/00909,respectively.
AvailabilityofdataandmaterialsNotapplicableAuthors'contributionPJWhadtheideaforthearticle,andcriticallyrevisedthemanuscript.
MAMdevelopedtheideaanddraftedthemanuscript.
ASz,AS,WJCandEScriticallyreviewedthemanuscriptforimportantcontent.
Allauthorsapprovedthefinalversionofthemanuscript.
EthicsapprovalandconsenttoparticipateNotapplicableConsentforpublicationNotapplicableCompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Publisher'sNoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.
Authordetails1DepartmentofHumanPhysiology,FacultyofHealthSciences,MedicalUniversityofGdansk,TuwimaStr.
15,80-210Gdansk,Poland.
2DepartmentofPsychiatry,FacultyofMedicine,MedicalUniversityofGdansk,Gdansk,Poland.
32-ndDepartmentofRadiology,FacultyofHealthSciences,MedicalUniversityofGdansk,Gdansk,Poland.
4DepartmentofClinicalAnatomyandPhysiology,FacultyofHealthSciences,PomeranianUniversityofSlupsk,Slupsk,Poland.
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