title: Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice.
abstract: The HD-N171-82Q (line 81) mouse model of Huntington's disease (HD), expresses an N-terminal fragment of mutant huntingtin (htt), loses motor function, displays HD-related pathological features, and dies prematurely. In the present study, we compare the efficacy with which environmental, pharmacological, and genetic interventions ameliorate these abnormalities. As previously reported for the R6/2 mouse model of HD, housing mice in enriched environments improved the motor skills of N171-82Q mice. However, life expectancy was not prolonged. Significant improvements in motor function, without prolonging survival, were also observed in N171-82Q mice treated with Coenzyme Q10 (CoQ10, an energy metabolism enhancer). Several compounds were not effective in either improving motor skills or prolonging life, including Remacemide (a glutamate antagonist), Celecoxib (a COX-2 inhibitor), and Chlorpromazine (a prion inhibitor); Celecoxib dramatically shortened life expectancy. We also tested whether raising cellular antioxidant capacity by co-expressing high levels of wild-type human Cu/Zn superoxide dismutase 1 (SOD1) was beneficial. However, no improvement in motor performance or life expectancy was observed. Although we would argue that positive outcomes in mice carry far greater weight than negative outcomes, we suggest that caution may be warranted in testing Celecoxib in HD patients. The positive outcomes achieved by CoQ10 therapy and environmental stimuli point toward two potentially therapeutic approaches that should be readily accessible to HD patients and at-risk family members.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. gschill1@jhem.jhmi.edu
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schilling
authors.forename: Alena V
authors.initials: AV
authors.lastname: Savonenko
authors.forename: Michael L
authors.initials: ML
authors.lastname: Coonfield
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Morton
authors.forename: Esther
authors.initials: E
authors.lastname: Vorovich
authors.forename: Alexa
authors.initials: A
authors.lastname: Gale
authors.forename: Christopher
authors.initials: C
authors.lastname: Neslon
authors.forename: Ning
authors.initials: N
authors.lastname: Chan
authors.forename: Michelle
authors.initials: M
authors.lastname: Eaton
authors.forename: David
authors.initials: D
authors.lastname: Fromholt
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000081:Acetamides / Q000627:therapeutic use; D000818:Animals; D000068579:Celecoxib; D002746:Chlorpromazine / Q000627:therapeutic use; D003067:Coenzymes; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D018492:Dopamine Antagonists / Q000627:therapeutic use; D004780:Environment, Controlled; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009048:Motor Skills / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010641:Phenotype; D011720:Pyrazoles; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D016896:Treatment Outcome; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000627:therapeutic use*
chemical_list: D000081:Acetamides; D003067:Coenzymes; D016861:Cyclooxygenase Inhibitors; D018492:Dopamine Antagonists; D018696:Neuroprotective Agents; D011720:Pyrazoles; C000606290:SOD1 protein, human; D013449:Sulfonamides; D014451:Ubiquinone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C067553:remacemide; C024989:coenzyme Q10; D000068579:Celecoxib; D002746:Chlorpromazine