Dexamethasoneisaglucocorticoidreceptoragonist.

Glucocorticoidreceptor^[1]

Dexamethasoneregulatesseveraltranscriptionfactors,includingactivatorprotein-1,nuclearfactor-AT,andnuclearfactor-kB,leADIngtotheactivationandrepressionofkeygenesinvolvedintheinflammatoryresponse^[1].Dexamethasonepotentlyinhibitsgranulocyte-macrophagecolonystimulatingfactor(GM-CSF)releasefromA549cellswithEC₅₀of2.2nM.Dexamethasone(EC₅₀=36nM)inducestranscriptionoftheβ₂-receptorisfoundtocorrelatewithglucocorticoidreceptor(GR)DNAbindingandoccurredat10-100foldhigherconcentrationsthantheinhibitionofGM-CSFrelease.Dexamethasone(IC₅₀=0.5nM)inhibitsa3×κB(NF-κB,IκBα,andI-κBβ),whichisassociatedwithinhibitionofGM-CSFrelease^[2].

IthaspreviouslybeenreportedthattreatmentwithDexamethasoneatadoseof2×5mg/kgefficientlyinhibitslipopolysaccharide(LPS)-inducedinflammation.Inourexperimentalsystem,treatmentwithasingledoseofDexamethasone10mg/kg(i.p.)significantlydecreasesrecruitmentofgranulocytesaswellasspontaneousproductionofoxygenradicalscomparedwithanimalsexposetoLPSandinjectedwithsolventalone(saline).Theeffectsarestatisticallysignificantwhenadministeredboth1hbeforeand1hafterinhalationofLPS.ThenumberofgranulocytesinBALFdecreasedtolevelscomparabletohealthyanimals(givenanaerosolofwater)^[3].RatstreatedwithDexamethasoneconsumelessfoodandweighedlessthancontrolrats.Treatedratsalsoweighlessthanpair-fedanimalsthoughtheirfoodintakeissimilar.FivedaysofDexamethasoneinjectionresultinasignificantincreaseinboththelivermass(+42%)andthelivertobodyweightratio(+65%).Thewetweightofgastrocnemiusmuscledecreases20%after5daysoftreatment,butitremainsunaffectedrelativetobodyweight(g/100gbodyweight),indicatingthatmuscleweightlossparalleledbodyweightloss^[4].

• [1].LaLoneCA,etal.Effectsofaglucocorticoidreceptoragonist,Dexamethasone,onfatheadminnowreproduction,growth,anddevelopment.EnvironToxicolChem.2012Mar;31(3):611-22.

  [2].AdcockIM,etal.Ligand-induceddifferentiationofglucocorticoidreceptor(GR)trans-repressionandtransactivation:preferentialtargettingofNF-kappaBandlackofI-kappaBinvolvement.BrJPharmacol.1999Jun;127(4):1003-11.

  [3].RocksénD,etal.Differentialanti-inflammatoryandanti-oxidativeeffectsofDexamethasoneandN-acetylcysteineinendotoxin-inducedlunginflammation.ClinExpImmunol.2000Nov;122(2):249-56.

  [4].RousselD,etal.Dexamethasonetreatmentspecificallyincreasesthebasalprotonconductanceofratlivermitochondria.FEBSLett.2003Apr24;541(1-3):75-9.

  [5].MaherHM,etal.Simultaneousdeterminationofselectedtyrosinekinaseinhibitorswithcorticosteroidsandantiemeticsinratplasmabysolidphaseextractionandultra-performanceliquidchromatography-tandemmassspectrometry:Applicationtopharmacokineticinteractionstudies.JPharmBiomedAnal.2016May30;124:216-27.

  [6].QixiongZhang,etal.Structure-PropertyCorrelationsofReactiveOxygenSpecies-ResponsiveandHydrogenPeroxide-EliminatingMaterialswithAnti-OxidantandAnti-InflammatoryActivities.ChemMater.2017,29(19):8221-8238.

Dexamethasoneispreparedinsaline(Mice)^[3].
Dexamethasoneispreparedin0.9%NaCl(Rat)^[4].

Mice^[3]
FemaleC57Bl/6JBommice(age10-12weeks)areusedinallexperiments.Dexamethasoneisadministeredasasingleinjectionof1or10mg/kg.Dexamethasoneisdissolvedinsalineand400μLareinjectedintraperitoneally,either1hbeforeor1hafterLPSexposure.Inoneexperiment,N-acetylcysteine(NAC)(100and500mg/kg)isinjectedsuccessivelyevery4•5h,starting1hbeforechallenge(fiveinjectionsintotal).AcontrolgroupofLPS-exposedanimalsareinjectedintraperitoneallywithsolventalone(saline).Intratrachealadministrationisperformedbyinstillationof100μLNAC(50,100or500mg/kg)orDexamethasone(10mg/kg)intothelungsofmiceanaesthetizedwith15mg/kgRapinovet(i.v.).
Rat^[4]
MaleSprague-Dawleyratsareused.Dexamethasone-treatedratsareinjectedintraperitoneallyoncedailywithDexamethasone(1.5mg/kgbodyweight)for5daysandareallowedtofeedadlibitum.TheDexamethasonedose(1.5mg/kg/day)andthedurationoftreatment(5days)arespecificallychosenasthistreatmentinducedareproducIBLeandmarkedcatabolicstate.Controlratsreceivednotreatmentandarefedadlibitum.InordertotakeintoaccountthedecreaseinfoodintakeinducedbyDexamethasonetreatment,athirdgroupofpair-fedratsareused.TheseratsareprovidedwiththesameamountoffoodasDexamethasone-injectedratsandaretreatedwithadailyisovolumicintraperitonealinjectionofNaCl(0.9%)for5days.AfterthefinalinjectionofDexamethasoneorNaCl,theanimalsarefastedovernightpriortobeingkilledbydecapitation.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].LaLoneCA,etal.Effectsofaglucocorticoidreceptoragonist,Dexamethasone,onfatheadminnowreproduction,growth,anddevelopment.EnvironToxicolChem.2012Mar;31(3):611-22.

  [2].AdcockIM,etal.Ligand-induceddifferentiationofglucocorticoidreceptor(GR)trans-repressionandtransactivation:preferentialtargettingofNF-kappaBandlackofI-kappaBinvolvement.BrJPharmacol.1999Jun;127(4):1003-11.

  [3].RocksénD,etal.Differentialanti-inflammatoryandanti-oxidativeeffectsofDexamethasoneandN-acetylcysteineinendotoxin-inducedlunginflammation.ClinExpImmunol.2000Nov;122(2):249-56.

  [4].RousselD,etal.Dexamethasonetreatmentspecificallyincreasesthebasalprotonconductanceofratlivermitochondria.FEBSLett.2003Apr24;541(1-3):75-9.

  [5].MaherHM,etal.Simultaneousdeterminationofselectedtyrosinekinaseinhibitorswithcorticosteroidsandantiemeticsinratplasmabysolidphaseextractionandultra-performanceliquidchromatography-tandemmassspectrometry:Applicationtopharmacokineticinteractionstudies.JPharmBiomedAnal.2016May30;124:216-27.

  [6].QixiongZhang,etal.Structure-PropertyCorrelationsofReactiveOxygenSpecies-ResponsiveandHydrogenPeroxide-EliminatingMaterialswithAnti-OxidantandAnti-InflammatoryActivities.ChemMater.2017,29(19):8221-8238.

392.46

C₂₂H₂₉FO₅

50-02-2

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO:≥56mg/mL

Invivo:insolubleinsaline(<0.1="">
Dexamethasone(DEX)sUSPensionispreparedseparatelybytrituratinganappropriateweightofDexamethasonewithaqueousmethylcellulose(0.5%,w/v)toformsuspensionswithconcentrationsof1.2mg/mL(DEX)^[5].
Dexamethasone(DXM)ispreparedinsaline^[6].

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

• [1].LaLoneCA,etal.Effectsofaglucocorticoidreceptoragonist,Dexamethasone,onfatheadminnowreproduction,growth,anddevelopment.EnvironToxicolChem.2012Mar;31(3):611-22.

  [2].AdcockIM,etal.Ligand-induceddifferentiationofglucocorticoidreceptor(GR)trans-repressionandtransactivation:preferentialtargettingofNF-kappaBandlackofI-kappaBinvolvement.BrJPharmacol.1999Jun;127(4):1003-11.

  [3].RocksénD,etal.Differentialanti-inflammatoryandanti-oxidativeeffectsofDexamethasoneandN-acetylcysteineinendotoxin-inducedlunginflammation.ClinExpImmunol.2000Nov;122(2):249-56.

  [4].RousselD,etal.Dexamethasonetreatmentspecificallyincreasesthebasalprotonconductanceofratlivermitochondria.FEBSLett.2003Apr24;541(1-3):75-9.

  [5].MaherHM,etal.Simultaneousdeterminationofselectedtyrosinekinaseinhibitorswithcorticosteroidsandantiemeticsinratplasmabysolidphaseextractionandultra-performanceliquidchromatography-tandemmassspectrometry:Applicationtopharmacokineticinteractionstudies.JPharmBiomedAnal.2016May30;124:216-27.

  [6].QixiongZhang,etal.Structure-PropertyCorrelationsofReactiveOxygenSpecies-ResponsiveandHydrogenPeroxide-EliminatingMaterialswithAnti-OxidantandAnti-InflammatoryActivities.ChemMater.2017,29(19):8221-8238.