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 journalArticle

142 Citations (Scopus)

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 (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
Volume93
Issue number2
DOIs
Publication statusPublished - Apr 2005
Externally publishedYes

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Huntington Disease
Transgenic Mice
AMP-Activated Protein Kinases
Heart Ventricles
Brain
Adenosine A2 Receptor Agonists
Neurodegenerative diseases
Adenosine A2A Receptors
Corpus Striatum
Intranuclear Inclusion Bodies
Ubiquitin
Choline
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
Neurodegenerative Diseases
Magnetic resonance imaging
Protein Kinases
Energy Metabolism
Deterioration
Blood Glucose
Exons

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. / Chou, Szu Yi; Lee, Yi Chao; Chen, Hui Mei; Chiang, Ming Chang; Lai, Hsing Lin; Chang, Hao Hung; Wu, Yi Chih; Sun, Chung Nan; Chien, Chen Li; Lin, Yow Sien; Wang, Shyi Chyi; Tung, Yu Ying; Chang, Chen; Chern, Yijuang.

In: Journal of Neurochemistry, Vol. 93, No. 2, 04.2005, p. 310-320.

Research output: Contribution to journalArticle

Chou, SY, Lee, YC, Chen, HM, Chiang, MC, Lai, HL, Chang, HH, Wu, YC, Sun, CN, Chien, CL, Lin, YS, Wang, SC, Tung, YY, Chang, C & Chern, Y 2005, 'CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model', Journal of Neurochemistry, vol. 93, no. 2, pp. 310-320. https://doi.org/10.1111/j.1471-4159.2005.03029.x
Chou, Szu Yi ; Lee, Yi Chao ; Chen, Hui Mei ; Chiang, Ming Chang ; Lai, Hsing Lin ; Chang, Hao Hung ; Wu, Yi Chih ; Sun, Chung Nan ; Chien, Chen Li ; Lin, Yow Sien ; Wang, Shyi Chyi ; Tung, Yu Ying ; Chang, Chen ; Chern, Yijuang. / CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. In: Journal of Neurochemistry. 2005 ; Vol. 93, No. 2. pp. 310-320.
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AU - Lai, Hsing Lin

AU - Chang, Hao Hung

AU - Wu, Yi Chih

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AU - Chien, Chen Li

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AU - Chang, Chen

AU - Chern, Yijuang

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