Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice

• Published in: Experimental neurology 2004-05, Vol.187 (1), p.137-149
• Main Authors: SCHILLING, Gabriele, SAVONENKO, Alena V, ROSS, Christopher A, BORCHELT, David R, COONFIELD, Michael L, MORTON, Johanna L, VOROVICH, Esther, GALE, Alexa, NESLON, Christopher, NING CHAN, EATON, Michelle, FROMHOLT, David
• Format: Article
• Language: English
• Subjects: Acetamides - therapeutic use; Animals; Biological and medical sciences; Celecoxib; Chlorpromazine - therapeutic use; Coenzymes; Cyclooxygenase Inhibitors - adverse effects; Cyclooxygenase Inhibitors - therapeutic use; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Disease Progression; Diseases of striated muscles. Neuromuscular diseases; Dopamine Antagonists - therapeutic use; Environment, Controlled; Female; Humans; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - physiopathology; Medical sciences; Mice; Mice, Transgenic; Motor Activity - drug effects; Motor Activity - genetics; Motor Skills - drug effects; Neurology; Neuroprotective Agents - pharmacology; Phenotype; Pyrazoles; Sulfonamides - adverse effects; Sulfonamides - therapeutic use; Superoxide Dismutase - biosynthesis; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Survival Rate; Treatment Outcome; Ubiquinone - analogs & derivatives; Ubiquinone - therapeutic use
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2004.01.003

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.