Seite - 30 - in Advances in Neuroimmunology

BrainSci. 2016,6, 6 mediatorof thehypoxic response that isdegradedinanoxygen-dependentmanner.Undernormoxic conditions,HIF-1αhasahalf-lifeofapproximately8mindue tohydroxylationbyprolylhydroxyl domains (PHDs) [5]. ThesePHDsexist in threedifferent isoforms,PHD1,PHD2,andPHD3andall requireoxygen, iron,ascorbateand2-oxoglutarate,aproductof theoxygendependentKrebcycle, to hydroxylateHIF-1α. Underhypoxicconditions theKrebcycle is inhbited leading toareduction in 2-oxoglutarate,preventingthebindingofPHDstothetargetingprolinedomains[4,6].Duringhypoxia, theHIF-1αprotein stabilizes allowing it to recruit transcriptional co-activators,whichareblocked during normal conditions via factor inhibitingHIF (FIH) [7]. This complex then permits for the transcriptionofhypoxia-relatedproteins throughbindingof thehypoxic responsiveelement (HRE). HREbinding induces theexpressionofgenes, suchaserythropoietin,vascularendothelialgrowth factorandinsulingrowthfactor. Theseallplayaneuroprotetiverole inresponse to thehypoxic insult. These acute and chronic responses to hypoxia are clearlymanifestedduring ischemic events in thebrain. Anexampleof one sucheventwith ahypoxic component is stroke,which is caused by a reduction in bloodflowas a result of an obstruction or rupture of blood vesselswithin the brainandmaycausebothacuteandchronicepisodesofhypoxia. This leads tocomplexpathological changes takingplace,whichmayleadto tissuenecrosis throughincreased inflammationandoxygen deprivation [8]. During an ischemic stroke the eventual restriction of oxygen in the braindue to anobstructionleadstoacascadeofeventsincludinghypoxia, increasedexpressionofpro-inflammatory cytokines like tumornecrosis factoralpha(TNF-α) andinterleukin-1beta (IL-1β), aswellas increased releaseof theexcitatoryneurotransmitterglutamate [9]. In this reviewwewilldiscusshowhypoxia andthereleaseofpro-inflammatorycytokinescaneffect synaptic transmissionandplasticity in the centralnervoussystem(CNS). 2.HypoxiaandSynapticSignaling SynaptictransmissionintheCNSrequiresapproximately30%to50%ofcerebraloxygen.Therefore manyof thechanges intheCNSrelatedtoacutehypoxiastemfrommodificationsofsynapticexcitation anddepression. Theresponsestohypoxia,whichoccurwithinseconds,most likelydonotinvolvearole forHIF-1αstabilization.Additionally,uponre-oxygenationafterashortperiod, synaptic transmission can recover to 100% inmanybrain regions [10]. This decrease in synaptic signalingduring acute hypoxia is thought to protect some neurons during ischemic events. Adenosine is one ofmany neurotransmitters,whichplaysavital role in theneuroprotectiveresponse tohypoxia [11].Adenosine A1 receptors (A1Rs), inparticular,playapart inalteringneurotransmitter release [12]andhavewide expression levels throughout theCNS[13]. This inhibitoryneuromodulationbyA1Rs is coupled to inhibitoryGi orGo containingG-proteins [14].Activationof thereceptorstimulatesadenylylcyclase, activatesinwardlyrectifyingK+channels, thusinhibitingCa2+channelsandactivationofphospholipase C.This inhibits thereleaseofanumberofneurotransmitters includingglutamate,dopamine, serotonin andacetylcholine thusmaking it theprimaryneuroprotective receptor. Adenosine forms through the enzymatic catabolismof adenosine triphosphate (ATP) into adenosinemonophosphate (AMP), whichthenisbrokendownbyecto’5nucelotidases intoadenosine(seeFigure1).Adenosinekinase is mainlyresponsible for theremovalofadenosineviaphosphorylation toAMP[15]. Underhypoxic conditionswhenthere isabuild-upofadenosine in theextracellularspace,hypoxia inducedfactors suchasHIF-1αalsocausean increase in theecto’5nucelotidasesCD73,allowingforabreakdownof extracellularATPintoadenosine [16,17]. It isnowknownthatduringhypoxia,HIF-1α inhibits theequilibrativenucleoside transporters ent-1/2locatedonthemembranesofneuronsandgliapreventingadenosinereuptakeintotheneuronal cell [18]. Extracellular adenosinebinds toA1Rs locatedonboth thepostsynaptic andpresynaptic membranes. PostsynapticA1Ractivationinhibits theactivationofglutamatergicN-methyl-D-aspartate receptors (NMDARs) and adenosine binding toA1Rs located presynaptically [14]. Inhibition of neurotransmitter release canbe suppressedby the addition of anA1R selective inhibitor, such as 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), suggestingthatadenosinebinding isnecessaryfor the 30