title: Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes.
abstract: Oxidative damage to mitochondria (MT) is a major mechanism for aging and neurodegeneration. We have developed a novel synthetic antioxidant, XJB-5-131, which directly targets MT, the primary site and primary target of oxidative damage. XJB-5-131 prevents the onset of motor decline in an HdhQ(150/150) mouse model for Huntington's disease (HD) if treatment starts early. Here, we report that XJB-5-131 attenuates or reverses disease progression if treatment occurs after disease onset. In animals with well-developed pathology, XJB-5-131 promotes weight gain, prevents neuronal death, reduces oxidative damage in neurons, suppresses the decline of motor performance or improves it, and reduces a graying phenotype in treated HdhQ(150/150) animals relative to matched littermate controls. XJB-5-131 holds promise as a clinical candidate for the treatment of HD.
authors.affiliation: Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720, USA.
authors.forename: Aris
authors.initials: A
authors.lastname: Polyzos
authors.affiliation: Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Holt
authors.affiliation: Molecular Cellular Biology Program, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brown
authors.affiliation: Molecular Cellular Biology Program, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Celica
authors.initials: C
authors.lastname: Cosme
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, Sant Joan d'Alacant, Spain and.
authors.forename: Alex
authors.initials: A
authors.lastname: Gomez-Marin
authors.affiliation: Department of Pharmacology and Toxicology, University of Puerto Rico, PO Box 365067, San Juan, PR 00936, USA.
authors.forename: Maríadel R
authors.initials: MR
authors.lastname: Castro
authors.affiliation: Department of Pharmacology and Toxicology, University of Puerto Rico, PO Box 365067, San Juan, PR 00936, USA.
authors.forename: Sylvette
authors.initials: S
authors.lastname: Ayala-Peña
authors.affiliation: Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720, USA, ctmcmurray@lbl.gov.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D003497:Cyclic N-Oxides; C523959:XJB-5-131