Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection 英文参考文献.docVIP

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Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection 英文参考文献.doc

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Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection 英文参考文献

FenofibrateReducesMortalityandPrecludes NeurologicalDeficitsinSurvivorsinMurineModelof JapaneseEncephalitisViralInfection NehaSehgal,KanhaiyaLalKumawat,AnirbanBasu,VijayalakshmiRavindranath* DivisionofMolecularandCellularNeuroscience,NationalBrainResearchCentre,NainwalMode,Manesar,Haryana,India Abstract Background:Japaneseencephalitis(JE),themostcommonformofviralencephalitisoccursperiodicallyinendemicareas leadingtohighmortalityandneurologicaldeficitsinsurvivors.Itiscausedbyaflavivirus,Japaneseencephalitisvirus(JEV), whichistransmittedtohumansthroughmosquitoes.Noeffectivecureexistsforreducingmortalityandmorbiditycaused byJEVinfection,whichisprimarilyduetoexcessiveinflammatoryresponse.Fenofibrate,aperoxisomeproliferator-activated receptor-a (PPARa) agonist is known to resolve inflammation by repressing nuclear factor-kB (NF-kB) and enhancing transcription of anti-oxidant and anti-inflammatory genes. In addition, fenofibrate also up-regulates a class of proteins, cytochromeP4504Fs(Cyp4fs),whichareinvolvedindetoxificationofthepotentpro-inflammatoryeicosanoid,leukotriene B4(LTB4)to20-hydroxyLTB4. Methodology/Principal Findings: Theneuroprotectiveeffectoffenofibratewasexaminedusingin vitro(BV-2microglial cellline)andinvivo(BALB/cmice)modelsofJEVinfection.Miceweretreatedwithfenofibratefor2or4dayspriortoJEV exposure.Pretreatmentwithfenofibratefor4butnot2daysreducedmortalityby80%andbrainLTB4 levelsdecreased concomitantly with the induction of Cyp4f15 and 4f18, which catalyze detoxification of LTB4 through hydroxylation. ExpressionofcytokinesandchemokinedecreasedsignificantlyasdidmicroglialactivationandreplicationoftheJEVvirus. Conclusions/Significance:FenofibrateconfersneuroprotectionagainstJapaneseencephalitis,invivo,inmousemodelof JEVinfection.Thus,fenofibrate,aPPARaagonistthatiscommonlyusedasahypolipidemicdrugcouldpotentiallybeused forprophylaxisduringJEepidemicstoreducemortalityandmorbidity. Citation:SehgalN,KumawatKL,BasuA,RavindranathV(2012)FenofibrateRe