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

Szu Yi Chou, Yi Chao Lee, Hui Mei Chen, Ming Chang Chiang, Hsing Lin Lai, Hao Hung Chang, Yi Chih Wu, Chung Nan Sun, Chen Li Chien, Yow Sien Lin, Shyi Chyi Wang, Yu Ying Tung, Chen Chang, Yijuang Chern

研究成果: 雜誌貢獻文章

146 引文 斯高帕斯(Scopus)

摘要

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 (A 2A-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.
原文英語
頁(從 - 到)310-320
頁數11
期刊Journal of Neurochemistry
93
發行號2
DOIs
出版狀態已發佈 - 四月 2005
對外發佈Yes

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Chou, S. Y., Lee, Y. C., Chen, H. M., Chiang, M. C., Lai, H. L., Chang, H. H., Wu, Y. C., Sun, C. N., Chien, C. L., Lin, Y. S., Wang, S. C., Tung, Y. Y., Chang, C., & Chern, Y. (2005). CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. Journal of Neurochemistry, 93(2), 310-320. https://doi.org/10.1111/j.1471-4159.2005.03029.x