title: Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis.
abstract: Reactive oxygen species (ROS) play a major role in the pathogenesis of neurodegenerative diseases. They are important contributors to necrotic and apoptotic cell death. A major proportion of cellular ROS is generated at the inner mitochondrial membrane by the respiratory chain. In the present study, we investigated a novel peptide antioxidant (SS-31) targeted to the inner mitochondrial membrane for its therapeutic effects both in vitro and in vivo in the G93A mouse model of amyotrophic lateral sclerosis (ALS). SS-31 protected against cell death induced by hydrogen peroxide in vitro in neuronal cells stably transfected with either wild-type or mutant Cu/Zn superoxide dismutase (SOD1). Daily intraperitoneal injections of SS-31 (5 mg/kg), starting at 30 days of age, led to a significant improvement in survival and motor performance. In comparison with vehicle-treated G93A mice, SS-31-treated mice showed a decreased cell loss and a decrease in immunostaining for markers of oxidative stress in the lumbar spinal cord. This further enhances the concept that pharmacological modification of oxidative stress is a therapeutic option for the treatment of ALS.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA. Petri.susanne@mh-hannover.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Maria
authors.initials: M
authors.lastname: Damiano
authors.forename: Andrew
authors.initials: A
authors.lastname: Hiller
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wille
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000375:Aging / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D001835:Body Weight / Q000502:physiology; D002452:Cell Count; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D000975:Antioxidants; D010455:Peptides; D017382:Reactive Oxygen Species; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1