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

Research output: Contribution to journalArticlepeer-review

162 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)310-320
Number of pages11
JournalJournal of Neurochemistry
Issue number2
Publication statusPublished - Apr 2005
Externally publishedYes


  • 5′AMP-activated protein kinase
  • A adenosine receptor; cAMP
  • CGS21680; Huntington's disease
  • R6/2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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