title: Uridine ameliorates the pathological phenotype in transgenic G93A-ALS mice.
abstract: There is strong evidence from studies in humans and animal models to suggest the involvement of energy metabolism defects in neurodegenerative diseases. Uridine, a pyrimidine nucleoside, has been suggested to be neuroprotective in neurological disorders by improving bioenergetic effects, increasing ATP levels and enhancing glycolytic energy production. We assessed whether uridine treatment extended survival and improved the behavioral and neuropathological phenotype observed in G93A-ALS mice. In vitro and in vivo pharmacokinetic analyses in mutant SOD models provided optimal dose and assurance that uridine entered the brain. A dose-ranging efficacy trial in G93A mice was performed using survival, body weight, open-field analysis, and neuropathology as outcome measures. Urinary levels of 8-hydroxy-2'-deoxyguanosine, identifying DNA oxidative damage, were measured and used as a pharmacodynamic biomarker. Uridine administration significantly extended survival in a dose-dependent manner in G93A mice, while improving the behavioral and neuropathological phenotype. Uridine increased survival by 17.4%, ameliorated body weight loss, enhanced motor performance, reduced gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Consistent with a therapeutic effect, uridine significantly reduced urinary 8-hydroxy-2'-deoxyguanosine in G93A mice. These data suggest that uridine may be a therapeutic candidate in ALS patients.
authors.affiliation: Geriatric Research Education Clinical Center, New England Veterans Administration, 200 Springs Road, Bedford, MA 01730, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Amante
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Samantha T
authors.initials: ST
authors.lastname: Carreiro
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Cooper
authors.forename: Steven W
authors.initials: SW
authors.lastname: Jones
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Moody
authors.forename: Christina K
authors.initials: CK
authors.lastname: Edgerly
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Bordiuk
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: James
authors.initials: J
authors.lastname: Rusche
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014529:Uridine / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D000080242:8-Hydroxy-2'-Deoxyguanosine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D003849:Deoxyguanosine; D014529:Uridine