title: Evaluation of NADPH oxidases as drug targets in a mouse model of familial amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons, gliosis, neuroinflammation and oxidative stress. The aim of this study was to evaluate the involvement of NADPH oxidases (NOX) in the oxidative damage and progression of ALS neuropathology. We examined the pattern of NOX expression in spinal cords of patients and mouse models of ALS and analyzed the impact of genetic deletion of the NOX1 and 2 isoforms as well as pharmacological NOX inhibition in the SOD1(G93A) ALS mouse model. 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 SOD1(G93A) 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 SOD1(G93A) 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 SOD1(G93A) mice in vivo. Yet, neither perphenazine nor thioridazine prolonged survival. Thioridazine, but not perphenazine, dampened the increase of microglia markers in SOD1(G93A) 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.
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland.
authors.forename: Tamara
authors.initials: T
authors.lastname: Seredenina
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Nayernia
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sorce
authors.affiliation: Victor Chang Cardiac Research Institute, Vascular Biology Division, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, NSW 2052, Australia.
authors.forename: Ghassan J
authors.initials: GJ
authors.lastname: Maghzal
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Filippova
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Physiology, National University of Singapore, Singapore.
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Basset
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Plastre
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Rushing
authors.affiliation: Department of Neuroscience, Medical School of the University of Turin, Italy.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Giordana
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.affiliation: Victor Chang Cardiac Research Institute, Vascular Biology Division, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, NSW 2052, Australia.
authors.forename: Roland
authors.initials: R
authors.lastname: Stocker
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland; Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland. Electronic address: Vincent.Jaquet@unige.ch.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jaquet
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D000074624:NADPH Oxidase 1 / Q000235:genetics*; D000074662:NADPH Oxidase 2 / Q000235:genetics* / Q000378:metabolism*; D010546:Perphenazine / Q000008:administration & dosage; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D013881:Thioridazine / Q000008:administration & dosage
chemical_list: C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; C000614711:NOX1 protein, mouse; D010546:Perphenazine; D013881:Thioridazine
keywords: Amyotrophic lateral sclerosis; Microglia; NADPH oxidase; NOX; Perphenazine; Phenothiazine; SOD1(G93A) mice; Thioridazine