CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model |
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Authors: | 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 |
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Institution: | Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. |
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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 A(2A) adenosine receptor (A(2A)-R)-selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D-microMRI analysis revealed that CGS reversed the enlarged ventricle-to-brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. (1)H-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. |
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Keywords: | 5'AMP-activated protein kinase A2A adenosine receptor cAMP CGS21680 Huntington's disease R6/2 |
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