Bile Acid Proves Neuroprotective in Huntington's Model
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A mitochondria-protecting, anti-apoptotic bile acid can reduce neurodegeneration and motor deficits in a mouse model of Huntington's disease, according to a report in the current Proceedings of the National Academy of Science. Noting that the compound has proven safe in other FDA-approved uses, the authors suggest it could be used as a therapy for other neurodegenerative disorders as well.
Coauthor Clifford Steer's molecular gastroenterology laboratory at the University of Minnesota in Minneapolis first discovered the anti-apoptotic properties of tauroursodeoxycholic acid (TUDCA). Subsequent work has shown that TUDCA is an antioxidant and that it inhibits mitochondrial processes that might contribute to neurodegeneration. In the present study, conducted with Walter Low, Dirk Keene, and other neuroscientists at Minnesota, TUDCA was administered to the R6/2 transgenic HD mouse, beginning at 6 weeks of age. Compared to untreated Tg mice, the treated mice showed less striatal atrophy, decreased striatal apoptosis and a reduction in abnormal huntingtin protein aggregates. More importantly, locomotor and sensorimotor deficits were significantly improved in the treated mice.
Also important was the fact that these results were achieved with systemic TUDCA, indicating that the compound can cross the blood/brain barrier. Given that TUDCA is produced endogenously and has shown few side-effects in its current uses in gastroenterologic disease, the authors propose that it could have potential in treating other neurodegenerative disorders that involve mitochondrial dysfunction, including Alzheimer's.—Hakon Heimer
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Primary Papers
- Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10671-6. PubMed.
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Weill Cornell Medical College
The recent study demonstrating that tauroursodeoxycholic acid exerts significant therapeutic effects in a transgenic mouse model of Huntington's Disease (HD) is extremely intriguing. This agent was previously demonstrated to stabilize mitochondria and inhibit release of cytochrome-c, which has been linked to apoptotic cell death. This prevents activation of downstream caspases. It is possible that similar mechanisms may play a role in Alzheimer's Disease (AD) pathogenesis. There is substantial evidence showing that a number of markers for apoptotic cell death are increased in AD postmortem brain tissue. There is also substantial evidence for mitochondrial dysfunction in AD. Decreases in cytochrome oxidase activity have been demonstrated both in postmortem as well as in peripheral tissues such as platelets. Reductions in alpha-ketoglutorate dehydrogenase activity are found in both fibroblasts as well as in brain tissue.
There is also a large body of evidence implicating increased oxidative damage in AD. All of these processes may be linked to mitochondrial dysfunction. Furthermore, mitochondrial dysfunction is linked to beta-amyloid production as recently demonstrated by Busciglio et al. Agents that can stabilize mitochondria and prevent their involvement in apoptotic cell death pathways may therefore be useful in treating a number of neurodegenerative diseases including AD.
References:
Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H, Yankner BA. Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron. 2002 Feb 28;33(5):677-88. PubMed.
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