Format

Send to

Choose Destination
Free Radic Biol Med. 2016 Aug;97:95-108. doi: 10.1016/j.freeradbiomed.2016.05.016. Epub 2016 May 19.

Evaluation of NADPH oxidases as drug targets in a mouse model of familial amyotrophic lateral sclerosis.

Author information

1
Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland.
2
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
3
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.
4
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.
5
Division of Clinical Pharmacology and Toxicology, Geneva University Hospital, Geneva, Switzerland.
6
Department of Neuroscience, Medical School of the University of Turin, Italy.
7
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.
8
Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland; Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Switzerland.
9
Department of Pathology and Immunology, Medical School, University of Geneva, Switzerland. Electronic address: Vincent.Jaquet@unige.ch.

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.

KEYWORDS:

Amyotrophic lateral sclerosis; Microglia; NADPH oxidase; NOX; Perphenazine; Phenothiazine; SOD1(G93A) mice; Thioridazine

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center