Global Inhibition of Reactive Oxygen Species (ROS) Inhibits Paclitaxel-Induced Painful Peripheral Neuropathy 英文参考文献.docVIP

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Global Inhibition of Reactive Oxygen Species (ROS) Inhibits Paclitaxel-Induced Painful Peripheral Neuropathy 英文参考文献.doc

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Global Inhibition of Reactive Oxygen Species (ROS) Inhibits Paclitaxel-Induced Painful Peripheral Neuropathy 英文参考文献

GlobalInhibitionofReactiveOxygenSpecies(ROS) InhibitsPaclitaxel-InducedPainfulPeripheral Neuropathy MehmetFidanboylu¤,LisaA.Griffiths,SarahJ.L.Flatters* WolfsonCentreforAge-RelatedDiseases,CentreforIntegrativeBiomedicine,King’sCollegeLondon,London,UnitedKingdom Abstract Paclitaxel(TaxolH)isawidelyusedchemotherapeuticagentthathasamajordoselimitingside-effectofpainfulperipheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies.Evidence formitochondrial dysfunction during paclitaxel-induced pain was previouslyindicated withthepresenceofswollenandvacuolatedneuronalmitochondria.Asmitochondriaareamajorsourceofreactiveoxygen species(ROS),theaimofthisstudywastoexaminewhetherpharmacologicalinhibitionofROScouldreverseestablished paclitaxel-inducedpainorpreventthedevelopmentofpaclitaxel-inducedpain.Usingaratmodelofpaclitaxel-inducedpain (intraperitoneal 2mg/kg paclitaxel on days 0, 2, 4 6), the effects of a non-specific ROS scavenger, N-tert-Butyl-a- phenylnitrone (PBN) anda superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were compared. Systemic 100mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8g and 15g stimulation and cold hypersensitivity to plantar acetone application. Daily systemicadministrationof50mg/kgPBN(days21to13)completelypreventedmechanicalhypersensitivitytovonFrey4g and8gstimulationandsignificantlyattenuatedmechanicalhypersensitivitytovonFrey15g.Systemic100mg/kgTEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250mg/kg) systemic TEMPOLsignificantlyinhibitedmechanicalhypersensitivitytovonFrey8g15g,buttoalesserextentthanPBN.Daily systemic administration of 100mg/kg TEMPOL (day 21 to 12) did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role