CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model
CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model
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DOI：
10.1111/j.1471-4159.2005.03029.x
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发表时间：
2005-04-01
影响因子：
4.7
通讯作者：
Chern, YJ
中科院分区：
文献类型：
--
作者：
Chou, SY;Lee, YC;Chern, YJ
亨廷顿病(HD)是一种常染色体显性遗传性神经退行性疾病，由亨廷顿蛋白(Huntingtin，Htt)基因第一外显子CAG三核苷酸扩增引起。我们在此表明，在HD转基因小鼠模型(R6/2)中，每天给予A(2A)腺苷受体(A(2A)-R)选择性激动剂CGS21680(CGS)，可以延缓运动能力的进行性恶化，并阻止脑重量的减轻。3D-MU MRI分析显示，CGS逆转了R6/2小鼠扩大的脑室与脑的比率，特别是左和右心室的改善。H-1-MRS显示CGS可显著降低纹状体胆碱水平的升高。免疫组织化学分析进一步表明，CGS减少了R6/2小鼠纹状体内泛素阳性神经元核内包涵体(NIIS)的大小，并改善了扩增多聚Q过表达突变型Htt的纹状体前体细胞系中突变型Htt的聚集。此外，慢性CGS治疗使升高的血糖水平正常化，并减少了R6/2小鼠纹状体中主要代谢感受器[5‘AMP激活蛋白激酶(AMPK)]的过度激活。由于AMPK是能量代谢的主开关，突变的Htt引起的能量功能障碍的调节可能有助于CGS的有益效果。总体而言，CGS是治疗HD的潜在候选药物。
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-mu MRI analysis revealed that CGS reversed the enlarged ventricle-to-brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. H-1-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.