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BrainSci. 2016,6, 6 Up-regulationof IL-1β is relatedtohypoxichyperexcitabilitydueto thefact that IL-1βcanactivate tyrosinekinases,which thenphosphorylate theNMDARsubunits,NR2AandNR2. This increase inNMDARpotentiation leads to excessiveflowofCa2+ leading tohyperexcitability andneuronal injury [52].Hypoxiaalso leads toactivationofnuclear factorκB(NFκB)signalingpathwayswhereby HIF-1αhasamolecular interactionwith the inflammatorymediatorNFκB.HREbinding,asseen in Figure2,allowsfor theexpressionofNFκB,whichthenactivates the transcriptionof inflammatory genes andHIFproteins [53]. NFκBexpression is increasedwhenhypoxia is followedbyaperiod of re-oxygenation [54]. Reactive oxygen species (ROS) have been shown to both activate and inactivateNFκB,whichcouldexplain the importanceof there-oxygenationperiod.ROScantrigger both apoptotic and necrotic cell death depending on the severity of the oxidative stress [55–57]. Another formofhypoxia,CIH,suchasseen insleepapneacan leadtoneuronalcelldeathandone of themechanisms involvedmay be inflammation. Neural inflammation caused byCIH can be regionspecificwith theexpressionofmicroglial toll-like receptor-4 (TLR4) increaseddifferentially acrossareasof theCNS[58].Hypoxia-re-oxygenation increasesmicroglial levelsof induciblenitric oxidesynthase (iNOS) leadingtoneuronalcell loss throughapoptosisandmemoryimpairment [59] Manyother insults suchasbacterial,viral, cytokinesandneurodegenerative insults induce iNOSin microglia [60]. This increase in iNOSraises the levelsofNOallowingfor the inhibitionofneuronal respirationcausingglutamaterelease [61]. Rho-associatedproteinkinase (ROCK) is thought toplay avital role in thispathwayas the introductionof theROCKinhibitor, fasudil, attenuates theneuronal apoptosis [62]. Thus inflammatorypathwaysandmicroglial activationarekeycomponents to the hypoxic responsewherebytheiractivationallowsfor formationofROSaswellashavingtheability to modulateglutamatergic receptors. The important role theyplay incausingneuronalcelldamageas well theirpotential tobeneuroprotective throughhypoxicpreconditioningmakes the inflammatory responseavital therapeutic target inhypoxia.Onlyrecentlyhas itbeenreportedthatpatientswith obstructivesleepapnea(involvingepisodesof IH)were1.37 timesmore likely tohaveParkinson’s disease thanpatientswithout thedisease [63]. Figure 2. Hypoxia and NFκB activation. During hypoxic HIF-1α binding to the HRE induces the expression ofNFκB (left). NFκBp50 p65 dimer is able to freely activate the transcription of inflammatoryandHIFproteins (right). 33