Antiviral and Neuroprotective Role of Octaguanidinium Dendrimer-Conjugated Morpholino Oligomers in Japanese Encephalitis 英文参考文献.docVIP

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Antiviral and Neuroprotective Role of Octaguanidinium Dendrimer-Conjugated Morpholino Oligomers in Japanese Encephalitis 英文参考文献.doc

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Antiviral and Neuroprotective Role of Octaguanidinium Dendrimer-Conjugated Morpholino Oligomers in Japanese Encephalitis 英文参考文献

AntiviralandNeuroprotectiveRoleofOctaguanidinium Dendrimer-ConjugatedMorpholinoOligomersin JapaneseEncephalitis ArshedNazmi.,KallolDutta.,AnirbanBasu* NationalBrainResearchCentre,Manesar,Haryana,India Abstract Background:Japaneseencephalitis(JE),causedbyamosquito-borneflavivirus,isendemictotheentiresouth-eastAsian and adjoining regions. Currently no therapeutic interventions are available for JE, thereby making it one of the most dreadedencephalitidesintheworld.Aneffectivewaytocountertheviruswouldbetoinhibitviralreplicationbyusinganti- sense molecules directed against the viral genome. Octaguanidinium dendrimer-conjugated Morpholino (or Vivo- Morpholino)areunchargedanti-senseoligomersthatcanentercellsoflivingorganismsbyendocytosisandsubsequently escapefromendosomesintothecytosol/nuclearcompartmentofcells.WehypothesizethatVivo-Morpholinosgenerated againstspecificregionsof39or59untranslatedregionsofJEVgenome,whenadministeredinanexperimentalmodelofJE, willhavesignificantantiviralandneuroprotectiveeffect. Methodology/PrincipalFindings:MicewereinfectedwithJEV(GP78strain)followedbyintraperitonealadministrationof Morpholinos(5mg/kgbodyweight)dailyforuptofivetreatments.Survivabilityoftheanimalswasmonitoredfor15days (or until death) following which they were sacrificed and their brains were processed either for immunohistochemical stainingorproteinextraction.Plaqueassayandimmunoblotanalysisperformedfrombrainhomogenatesshowedreduced viralloadandviralproteinexpression,resultingingreatersurvivalofinfectedanimals.Neuroprotectiveeffectwasobserved bythioninstainingofbrainsections.Cytokinebeadarrayshowedreductioninthelevelsofproinflammatorycytokinesin brain following Morpholino treatment, which were elevated after infection. This corresponded to reduced microglial activationinbrain.Oxidativestresswasreducedandcertainstress-relatedsignalingmoleculeswerefoundtobepositively modulatedfollowingMorpholinotreatment.Invitrostudiesalsoshowedthattherewasdecreaseininfectiveviralparticle pr