Uridine ameliorates the pathological phenotype in transgenic G93A-ALS mice
Autor: | Steven W. Jones, Andrew C Cooper, Jinho Kim, Karen L. Smith, Kerry Cormier, James R. Rusche, Samantha T Carreiro, Robert J. Ferrante, Olivia L. Bordiuk, Jennifer P. Moody, Ting Li, Christina K. Edgerly, Daniel J. Amante |
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Rok vydání: | 2010 |
Předmět: |
Male
Mice Transgenic Kaplan-Meier Estimate Biology Pharmacology Neuroprotection Rats Sprague-Dawley chemistry.chemical_compound Mice Random Allocation Atrophy In vivo Anterior Horn Cells medicine Deoxyguanosine Animals Humans Uridine Behavior Animal Dose-Response Relationship Drug Superoxide Dismutase Amyotrophic Lateral Sclerosis Body Weight 8-Hydroxy-2'-deoxyguanosine General Medicine medicine.disease Astrogliosis Rats Mice Inbred C57BL Survival Rate Disease Models Animal Neuroprotective Agents Neurology chemistry Spinal Cord 8-Hydroxy-2'-Deoxyguanosine Neurology (clinical) Energy Metabolism Nucleoside |
Zdroj: | Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 11(6) |
ISSN: | 1471-180X |
Popis: | 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. |
Databáze: | OpenAIRE |
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