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brain sciences Article PriorBingeEthanolExposurePotentiates the MicroglialResponseinaModelof Alcohol-InducedNeurodegeneration SimonAlexMarshall 1,ChelseaRheaGeil 2 andKimberlyNixon2,* 1 DepartmentofPsychology&Neuroscience;UniversityofNorthCarolina-ChapelHill,ChapelHill, NC27599,USA;simon.alexm@unc.edu 2 DepartmentofPharmaceuticalSciences,CollegeofPharmacy,UniversityofKentucky,Lexington, KY40536,USA;chelsea.geil@uky.edu * Correspondence: kim-nixon@uky.edu;Tel.:+1-859-215-1025 AcademicEditor:DonnaGruol Received: 5April2016;Accepted: 16May2016;Published: 26May2016 Abstract:Excessivealcoholconsumptionresults inneurodegenerationwhichsomehypothesize is causedbyneuroinflammation. One characteristic of neuroinflammation ismicroglial activation, but it is nowwell accepted thatmicroglial activationmaybepro- or anti-inflammatory. Recent work indicates that the Majchrowicz model of alcohol-induced neurodegeneration results in anti-inflammatorymicroglia,while intermittentexposuremodelswith lowerdosesandbloodalcohol levelsproducemicrogliawithapro-inflammatoryphenotype. Todetermine theeffectofarepeated bingealcoholexposure, ratsreceivedtwocyclesof thefour-dayMajchrowiczmodel.Onehemisphere wasthenusedtoassessmicrogliaviaimmunohistochemistryandwhiletheotherwasusedforELISAs ofcytokinesandgrowthfactors.Asinglebingeethanolexposureresulted in low-levelofmicroglial activation;however,asecondbingepotentiatedthemicroglial response. Specifically,doublebinge rats hadgreaterOX-42 immunoreactivity, increased ionized calcium-bindingadaptermolecule 1 (Iba-1+) cells, andupregulated tumornecrosis factor-α (TNF-α) comparedwith the single binge ethanolgroup.Thesedata indicate thatpriorethanolexposurepotentiatesasubsequentmicroglia response,whichsuggests that the initial exposure toalcoholprimesmicroglia. Insummary, repeated ethanolexposure, independentofother immunemodulatoryevents,potentiatesmicroglialactivity. Keywords: alcohol; ethanol; microglia; cytokines; TNF-alpha; alcoholism; microglial priming; neurodegeneration 1. Introduction Nearly 14%of theUnited States populationmeets the diagnostic criteria for an alcohol use disorder (AUD)inanygivenyear [1]. Excessivealcoholconsumptionproducesneurodegeneration inhumans [2–4], aneffect thathasbeenconfirmed invariouspre-clinicalmodels [5–8]. Due to its preventablenature,alcoholismtraditionallyhasnotbeendefinedasaneurodegenerativedisorder,but chronic, excessiveconsumptionmaycausedamage in the temporal lobeonparwithdiseases such asAlzheimer’s [4]. Indeed, alcoholic-relateddementia is the second leading causeofdementia in theUnitedStatesonlybehindAlzheimer’sdisease [9,10]. Evenin theabsenceofdementia, cognitive deficitssuchas increasedimpulsivityandimpairedexecutivedecision-makingarefoundinmanywith AUDs[11,12].Alcohol-inducedneurodegenerationandtheassociatedcognitivedeficitsare thought to becritical factors in thedevelopmentofAUDs[13–15]. BrainSci. 2016,6, 16 64 www.mdpi.com/journal/brainsci