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

Gabriele Schilling, Alena V. Savonenko, Michael L. Coonfield, Johanna L. Morton, Esther Vorovich, Alexa Gale, Christopher Neslon, Ning Chan, Michelle Eaton, David Fromholt, Christopher A. Ross, David R. Borchelt

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)137-149
Number of pages13
JournalExperimental Neurology
Volume187
Issue number1
DOIs
StatePublished - May 1 2004

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Keywords

  • Coenzyme Q10
  • Drug trial
  • Environmental enrichment
  • HD-N171-82Q transgenic mice
  • Huntington's disease
  • Remacemide hydrochloride

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Schilling, G., Savonenko, A. V., Coonfield, M. L., Morton, J. L., Vorovich, E., Gale, A., Neslon, C., Chan, N., Eaton, M., Fromholt, D., Ross, C. A., & Borchelt, D. R. (2004). Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice. Experimental Neurology, 187(1), 137-149. https://doi.org/10.1016/j.expneurol.2004.01.003