A bile acid protects against motor and cognitive deficits and reduces striatal degeneration in the 3-nitropropionic acid model of Huntington's disease

C. Dirk Keene, Cecilia M.P. Rodrigues, Tacjana Eich, Cheryle Linehan-Stieers, Anna Abt, Betsy T. Kren, Clifford J Steer, Walter C Low

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88 Scopus citations

Abstract

There is currently no effective treatment for Huntington's disease (HD), a progressive, fatal, neurodegenerative disorder characterized by motor and cognitive deterioration. It is well established that HD is associated with perturbation of mitochondrial energy metabolism. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, can stabilize the mitochondrial membrane, inhibit the mitochondrial permeability transition, decrease free radical formation, and derail apoptotic pathways. Here we report that TUDCA significantly reduced 3-nitropropionic acid (3-NP)-mediated striatal neuronal cell death in cell culture. In addition, rats treated with TUDCA exhibited an 80% reduction in apoptosis and in lesion volumes associated with 3-NP administration. Moreover, rats which received a combination of TUDCA + 3-NP exhibited sensorimotor and cognitive task performance that was indistinguishable from that of controls, and this effect persisted at least 6 months. Bile acids have traditionally been used as therapeutic agents for certain liver diseases. This is the first demonstration, however, that a bile acid can be delivered to the brain and function as a neuroprotectant and thus may offer potential therapeutic benefit in the treatment of certain neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)351-360
Number of pages10
JournalExperimental Neurology
Volume171
Issue number2
DOIs
StatePublished - 2001

Bibliographical note

Funding Information:
We thank the Electron Microscopy Facility in the Department of Molecular and Cellular Biology and Genetics; Jerry Sedgewick and the Biomedical and Image Processing Laboratory; and Steve Spell-man, Susana Solá, Sampson Ndikum, Xiaoming Ma, Wei-Jun Wang, and Bill Kaemmerer for technical assistance. This work was supported by the Lyle French Fund, PRAXIS/C/SAU/14311/1998 (C.M.P.R.), and NIMH Predoctoral NRSA 5F30MH12157-02 (C.D.K.).

Keywords

  • 3-nitropropionic acid
  • Apoptosis
  • Bile acid
  • Huntington's disease
  • Mitochondria
  • Neuroprotection
  • Striatum
  • Tauroursodeoxycholic acid

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