Seite - 55 - in Advances in Neuroimmunology

BrainSci. 2016,6, 41 with advancedpathology. Elevated levels ofpro-inflammatory cytokineshavealsobeendetected in the cerebrospinalfluidandplasmaofPDpatients at early stagesof thedisease. Thesefindings suggest thatmicroglial activationmaybe initiated in early stages and remain anongoingprocess throughout thedisease. Furthermore, inflammatory insultsandinjuriesareknownto increase therisk ofdevelopingPD.Traumaticbrain injuries (TBI)havebeen linkedtoan increasedriskofdeveloping thedisease in a frequency and severitydependentmanner;multiple injuries or injuries requiring hospitalizationweremorestronglycorrelatedwithPDonset [27]. Thisoccurrence is largelyattributed to theneuroinflammatorycascade that followstrauma.Certain infectionscausingneuroinflammation havebeenknownto leadtoapost-encephaliticParkinsonism.Thismaybebecause theSNisdensely populatedbymicroglia[28], renderingit isespeciallysusceptibletoinflammatorystimuli. Forexample, intracranial injectionsof lipopolysaccharide (LPS),abacterialantigen,dramaticallyactivatemicroglia andleads tonigrostriataldegenerationandmotorsymptomsofPD[29]. Parkinsonismisaseparate conditiondistinct fromPD,but theseobservationsof inflammatory insults leadingtocelldeathmay have important implications for PD itself. Taken together, these data suggest a potential role of neuroinflammation inongoingcelldeath thatoccurs inPD. Furthermore,pathological formsofα-synareassociatedwithmicroglialactivationinthebrainsof PDpatientsandthis is consistentlyrecapitulated inanimalmodels. Thepresenceofα-synaggregates modulates glial activity, often eliciting the release of inflammatorymediators. Codoloetal. (2013) treatedmonocyteswithvariousspeciesofα-syntodemonstrate that theaggregatedandpathogenic formsof theproteincanfacilitate thesecretionof IL-1β thoughstimulationof the inflammasome[30]. Thenitrationofα-syn isacommonmodificationassociatedwithpathologythought tobepromoted in anoxidativeenvironment. Stimulationofmicroglial cellswithnitratedandaggregatedα-synalters thecellularmorphologyandtranscriptionalprofile toapro-inflammatoryphenotype,with increased transcriptionof IL-1β,TNF-α, andIFN-γaswellas inductionofNF-Kβsignaling[31].Additionally, thisα-synactivationofmicrogliaseemstoberelatedtophagocyticcapacity,as inflammatorycascades andactivationofNADPHoxidaseare initiatedafter theglial cells takeup theaggregates [3,32,33]. Zhanget al. (2005)demonstrated that impedingphagocytosisofprimarymicroglia attenuates the releaseofsuperoxide fromthesecellswhenexposedtoα-syn invitro. Thisdetectionandengulfment of α-syn seems to be dependent on the FCγ receptor, as FCγ deficient mice are protected the resultantneurodegenerationfromAAVdrivenoverexpressionofα-syn[32,33]. It is thought that this inflammatoryresponse toabnormalα-synwillperpetuateneuraldysfunctionthroughthereleaseof cytotoxiccompoundsthat leads tocelldeath.Manyof thesestudiesweredoneusingeitherglial cell linesor inyounganimals,neglectingthe impactof thepro-inflammatoryactionsofα-synwithin the primedglialenvironmentofanagingbrain, thuscausingevenmoredamage. In fact,whenα-syn is introducedintoanagedanimal it ismorecytotoxiccomparedto theyoungcontrols [34]. 4. FractalkineasanAnti-InflammatoryTreatment There is promisingpre-clinical experimental evidence to support that reducing inflammation, specifically by suppressing microglial activity, can modify the progression of the loss of DA neurons[35–38].Non-steroidalanti-inflammatorydrugshavebeensuggestedtoreduce theriskofPD onset [39].Also, theuseofminocycline,a tetracyclinewithpharmaceuticalactions thatextendbeyond theclassicalantimicrobialactivity,hasbeenshowntoreducecelldeathinaneurotoxicmodelofPDusing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).Theseresearchersattributedtheneuroprotective effect to thedown-regulationof iNOSexpressionandglialactivation[40].Minocyclinewasalsoshown toinhibitapoptosis throughareductionofrelatedinflammatorymediators [41]. Becauseglialactivation is associatedwith the release of pro-inflammatory factors capable of damagingneurons, this data suggests thatmediatingtheexcessive inflammationinPDisaviable therapeuticstrategy. Thereare several signalsproducedbyneurons thathaveananti-inflammatoryactiononmicroglia, including CD200,CD22,CD47andfractalkine (FKN,CX3CL1),whichcouldbepotential therapeutic targets. 55