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CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model

CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. We show herein that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an A2A adenosine receptor (A2A‐R)‐selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D‐µMRI analysis revealed that CGS reversed the enlarged ventricle‐to‐brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. 1H‐MRS showed that CGS significantly reduced the increased choline levels in the striatum. Immunohistochemical analyses further demonstrated that CGS reduced the size of ubiquitin‐positive neuronal intranuclear inclusions (NIIs) in the striatum of R6/2 mice and ameliorated mutant Htt aggregation in a striatal progenitor cell line overexpressing mutant Htt with expanded polyQ. Moreover, chronic CGS treatment normalized the elevated blood glucose levels and reduced the overactivation of a major metabolic sensor [5′AMP‐activated protein kinase (AMPK)] in the striatum of R6/2 mice. Since AMPK is a master switch for energy metabolism, modulation of energy dysfunction caused by the mutant Htt might contribute to the beneficial effects of CGS. Collectively, CGS is a potential drug candidate for the treatment of HD. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurochemistry Wiley

CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model

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References (63)

Publisher
Wiley
Copyright
"Copyright © 2005 Wiley Subscription Services, Inc., A Wiley Company"
ISSN
0022-3042
eISSN
1471-4159
DOI
10.1111/j.1471-4159.2005.03029.x
pmid
15816854
Publisher site
See Article on Publisher Site

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. We show herein that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an A2A adenosine receptor (A2A‐R)‐selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D‐µMRI analysis revealed that CGS reversed the enlarged ventricle‐to‐brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. 1H‐MRS showed that CGS significantly reduced the increased choline levels in the striatum. Immunohistochemical analyses further demonstrated that CGS reduced the size of ubiquitin‐positive neuronal intranuclear inclusions (NIIs) in the striatum of R6/2 mice and ameliorated mutant Htt aggregation in a striatal progenitor cell line overexpressing mutant Htt with expanded polyQ. Moreover, chronic CGS treatment normalized the elevated blood glucose levels and reduced the overactivation of a major metabolic sensor [5′AMP‐activated protein kinase (AMPK)] in the striatum of R6/2 mice. Since AMPK is a master switch for energy metabolism, modulation of energy dysfunction caused by the mutant Htt might contribute to the beneficial effects of CGS. Collectively, CGS is a potential drug candidate for the treatment of HD.

Journal

Journal of Neurochemistry – Wiley

Published: Apr 1, 2005

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