title: Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron degeneration that ultimately results in progressive paralysis and death. Growing evidence indicates that mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in ALS. To further explore the hypothesis that mitochondrial dysfunction and nitroxidative stress contribute to disease pathogenesis at the in vivo level, we assessed whether the mitochondria-targeted antioxidant [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methane sulfonate (MitoQ) can modify disease progression in the SOD1(G93A) mouse model of ALS. To do this, we administered MitoQ (500 µM) in the drinking water of SOD1(G93A) mice from a time when early symptoms of neurodegeneration become evident at 90 days of age until death. This regime is a clinically plausible scenario and could be more easily translated to patients as this corresponds to initiating treatment of patients after they are first diagnosed with ALS. MitoQ was detected in all tested tissues by liquid chromatography/mass spectrometry after 20 days of administration. MitoQ treatment slowed the decline of mitochondrial function, in both the spinal cord and the quadriceps muscle, as measured by high-resolution respirometry. Importantly, nitroxidative markers and pathological signs in the spinal cord of MitoQ-treated animals were markedly reduced and neuromuscular junctions were recovered associated with a significant increase in hindlimb strength. Finally, MitoQ treatment significantly prolonged the life span of SOD1(G93A) mice. Our results support a role for mitochondrial nitroxidative damage and dysfunction in the pathogenesis of ALS and suggest that mitochondria-targeted antioxidants may be of pharmacological use for ALS treatment.
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Miquel
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cassina
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez-Palma
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: José M
authors.initials: JM
authors.lastname: Souza
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: Carmen
authors.initials: C
authors.lastname: Bolatto
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Rodríguez-Bottero
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.affiliation: Department of Chemistry, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay.
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.affiliation: Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay. Electronic address: pcassina@fmed.edu.uy.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cassina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D014451:Ubiquinone; C429014:mitoquinone
keywords: Amyotrophic lateral sclerosis; Antioxidants; Free radicals; MitoQ; Mitochondria; Nitroxidative stress