Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8267520 | Free Radical Biology and Medicine | 2016 | 47 Pages |
Abstract
A substantial (10-60 times) increase of NOX2 expression was detected in three etiologically different ALS mouse models while up-regulation of some other NOX isoforms was model-specific. In human spinal cord samples, high NOX2 expression was detected in microglia. In contrast to previous publications, survival of SOD1G93A mice was not modified upon breeding with constitutive NOX1 and NOX2 deficient mice. As genetic deficiency of a single NOX isoform is not necessarily predictive of a pharmacological intervention, we treated SOD1G93A mice with broad-spectrum NOX inhibitors perphenazine and thioridazine. Both compounds reached in vivo CNS concentrations compatible with NOX inhibition and thioridazine significantly decreased superoxide levels in the spinal cord of SOD1G93A mice in vivo. Yet, neither perphenazine nor thioridazine prolonged survival. Thioridazine, but not perphenazine, dampened the increase of microglia markers in SOD1G93A mice. Thioridazine induced an immediate and temporary enhancement of motor performance (rotarod) but its precise mode of action needs further investigation. Additional studies using specific NOX inhibitors will provide further evidence on the relevance of NOX as drug targets for ALS and other neurodegenerative disorders.
Keywords
DPIHOClHBSSNADPHDUOXGM-CSFWST-1EC50qPCRSOD1G93A miceFBSTAR DNA binding protein 43DMEMNoxO12-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium saltPBS2-OH-E+2-hydroxyethidiumMPODMSODNADulbecco's modified Eagle MediumFUS/TLSLC/MS/MSPMANOxROSHydrogen peroxideSuperoxide radical anionEthidiumamyotrophic lateral sclerosisdeoxyribonucleic acidhypochlorous acidNADPH oxidaseALSThioridazineCNSdual oxidaseDiphenyleneiodoniumDimethylsulfoxideSODblood brain barrierBBBfetal bovine serumSuperoxide dismutasecentral nervous systemLiquid chromatography-tandem mass spectrometrygranulocyte-macrophage colony-stimulating factorphorbol myristate acetatePhosphate buffered salinePhenothiazineHank's buffered salt solutionmyeloperoxidaseMicrogliawild typenicotinamide adenine dinucleotide phosphateHydroethidineH2O2quantitative polymerase chain reactionPerphenazineReactive oxygen species
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Authors
Tamara Seredenina, Zeynab Nayernia, Silvia Sorce, Ghassan J. Maghzal, Aleksandra Filippova, Shuo-Chien Ling, Olivier Basset, Olivier Plastre, Youssef Daali, Elisabeth J. Rushing, Maria T. Giordana, Don W. Cleveland, Adriano Aguzzi, Roland Stocker,