title: CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model.
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.
authors.affiliation: Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Szu-Yi
authors.initials: SY
authors.lastname: Chou
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.forename: Hsing-Lin
authors.initials: HL
authors.lastname: Lai
authors.forename: Hao-Hung
authors.initials: HH
authors.lastname: Chang
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Wu
authors.forename: Chung-Nan
authors.initials: CN
authors.lastname: Sun
authors.forename: Chen-Li
authors.initials: CL
authors.lastname: Chien
authors.forename: Yow-Sien
authors.initials: YS
authors.lastname: Lin
authors.forename: Shyi-Chyi
authors.initials: SC
authors.lastname: Wang
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Tung
authors.forename: Chen
authors.initials: C
authors.lastname: Chang
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D010627:Phenethylamines / Q000627:therapeutic use*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine