title: Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice.
abstract: There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.
authors.affiliation: Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford 01730, and Neurology Department, Boston University School of Medicine, MA 02180, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Smith
authors.forename: Samantha
authors.initials: S
authors.lastname: Matson
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Matson
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Del Signore
authors.forename: Sean W
authors.initials: SW
authors.lastname: Hagerty
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D003067:Coenzymes; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000166:cytology / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000276:immunology; D018696:Neuroprotective Agents; D009687:Nuclear Proteins / Q000276:immunology; D045442:Rotarod Performance Test; D016896:Treatment Outcome; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D003067:Coenzymes; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D014451:Ubiquinone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000255:Adenosine Triphosphate; C024989:coenzyme Q10; D003849:Deoxyguanosine; C030571:ubiquinone 9