CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model

J Neurochem. 2005 Apr;93(2):310-20. doi: 10.1111/j.1471-4159.2005.03029.x.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / therapeutic use*
  • Adenosine A2 Receptor Agonists
  • Animals
  • Brain / drug effects
  • Brain / pathology
  • Disease Models, Animal*
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Huntington Disease / prevention & control*
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Phenethylamines / therapeutic use*

Substances

  • Adenosine A2 Receptor Agonists
  • Phenethylamines
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • Adenosine