Efficacy of Different Nitric Oxide-Based Strategies in Preventing Experimental Cerebral Malaria by Plasmodium berghei ANKA 英文参考文献.docVIP

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Efficacy of Different Nitric Oxide-Based Strategies in Preventing Experimental Cerebral Malaria by Plasmodium berghei ANKA 英文参考文献.doc

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Efficacy of Different Nitric Oxide-Based Strategies in Preventing Experimental Cerebral Malaria by Plasmodium berghei ANKA 英文参考文献

EfficacyofDifferentNitricOxide-BasedStrategiesin PreventingExperimentalCerebralMalariaby PlasmodiumbergheiANKA YuriC.Martins1,2*,GrazielaM.Zanini1,3,JohnA.Frangos1,LeonardoJ.M.Carvalho1,4 1CenterforMalariaResearch,LaJollaBioengineeringInstitute,SanDiego,California,UnitedStatesofAmerica,2LaboratoryofInflammationandImmunity,Instituteof Microbiology,FederalUniversityofRiodeJaneiro,RiodeJaneiro,Brazil,3ParasitologyService,EvandroChagasClinicalResearchInstitute,Fiocruz,RiodeJaneiro,Brazil, 4LaboratoryofMalariaResearch,OswaldoCruzInstitute,Fiocruz,RiodeJaneiro,Brazil Abstract Background: Low nitric oxide (NO) bioavailability plays a role in the pathogenesis of human as well as of experimental cerebralmalaria(ECM)causedbyPlasmodiumbergheiANKA(PbA).ECMispartiallypreventedbyadministrationoftheNO- donordipropylenetriamineNONOate(DPTA-NO)athighconcentration(1mg/mouse),whichalsoinducesmajorsideeffects suchasasharpdropinbloodpressure.WeaskedwhetheralternativestrategiestoimproveNObioavailabilitywithminor sideeffectswouldalsobeeffectiveinpreventingECM. Methodology/Principal Findings: Mice were infected with PbA and prophylactically treated twice a day with bolus injectionsofL-arginine,Nv-hydroxy-nor-Arginine(nor-NOHA),tetrahydrobiopterin(BH4),separatelyorcombined,sodium nitrite, sildenafil or sildenafil plus DPTA-NO starting on day 0 of infection. L-arginine and BH4 supplementation, with or withoutarginaseinhibitionbynor-NOHA,increasedplasmanitritelevelsbutfailedtoprotectagainstECMdevelopment. Accordingly, prophylactic treatment with continuous delivery of L-arginine using osmotic pumps also did not improve survival.Similaroutcomeswereobservedwithsodiumnitritesildenafil(aimedatinhibitingphosphodiesterase-5)orwith DPTA-NO. However, sildenafil (0.1mg/mouse) in combination with a lower dose (0.1mg/mouse) of DPTA-NO decreased ECM incidence (8267.4% mortality in the saline group and 38610.6% in the treated group; p,0.05). The combined prophylactictherapydidnotaggravateanemia,haddelay