title: Targeting of XJB-5-131 to mitochondria suppresses oxidative DNA damage and motor decline in a mouse model of Huntington's disease.
abstract: Oxidative damage and mitochondrial dysfunction are implicated in aging and age-related neurodegenerative diseases, including Huntington's disease (HD). Many naturally occurring antioxidants have been tested for their ability to correct for deleterious effects of reactive oxygen species, but often they lack specificity, are tissue variable, and have marginal efficacy in human clinical trials. To increase specificity and efficacy, we have designed a synthetic antioxidant, XJB-5-131, to target mitochondria. We demonstrate in a mouse model of HD that XJB-5-131 has remarkably beneficial effects. XJB-5-131 reduces oxidative damage to mitochondrial DNA, maintains mitochondrial DNA copy number, suppresses motor decline and weight loss, enhances neuronal survival, and improves mitochondrial function. The findings poise XJB-5-131 as a promising therapeutic compound.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Zhiyin
authors.initials: Z
authors.lastname: Xun
authors.forename: Sulay
authors.initials: S
authors.lastname: Rivera-Sánchez
authors.forename: Sylvette
authors.initials: S
authors.lastname: Ayala-Peña
authors.forename: James
authors.initials: J
authors.lastname: Lim
authors.forename: Helen
authors.initials: H
authors.lastname: Budworth
authors.forename: Erin M
authors.initials: EM
authors.lastname: Skoda
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D018628:Gene Dosage; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D004272:DNA, Mitochondrial; C523959:XJB-5-131