CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model.
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.
Chou
Szu-Yi
SY
Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Lee
Yi-Chao
YC
Chen
Hui-Mei
HM
Chiang
Ming-Chang
MC
Lai
Hsing-Lin
HL
Chang
Hao-Hung
HH
Wu
Yi-Chih
YC
Sun
Chung-Nan
CN
Chien
Chen-Li
CL
Lin
Yow-Sien
YS
Wang
Shyi-Chyi
SC
Tung
Yu-Ying
YY
Chang
Chen
C
Chern
Yijuang
Y
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*
D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine