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-lMRI 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.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Functionally, CGS treatment reversed the elevated choline/creatine ratio (indicative of metabolic impairment and neurodegeneration) and reduced the activation of 5′AMP-activated protein kinase (AMPK), a major metabolic sensor and downstream mediator of stress-induced pathways, suggesting that CGS-induced activation of A2a receptors modulates abnormal metabolic pathways in R6/2 mice. In agreement with an improved energy metabolism, CGS administration also decreased the elevated blood glucose levels in diabetic R6/ 2 mice (Chou et al, 2005). Further experiments will be needed to evaluate the effects of an early administration of this compound on survival, body weight and frequency of NIIs in the R6/2 mouse model.…”

“…In early stages of HD (grade 0) there is a major loss of excitatory A2a receptor [abundant in striatal γ-aminobutyric acid (GABA)-containing neurons] binding in the caudate nucleus, putamen and globus pallidus externus (Glass et al, 2000). Thus, the potential benefits of CGS21680 (CGS; a selective agonist of adenosine A2a receptors) were evaluated in the R6/2 HD mouse model (Chou et al, 2005). Daily i.p.…”

“…At the electrophysiological level, SCH 58261 treatment abolished the increase in N-methyl-D-aspartate (NMDA)-induced toxicity in R6/2 corticostriatal slices (Domenici et al, 2007). Because the results obtained by either activating (Chou et al, 2005) or inhibiting (Domenici et al, 2007) adenosine A2a receptors at similar symptomatic phases of the disease (5 or 7 week-old) were found to trigger neuroprotective effects in R6/2 mice, one may deduce that A2a receptors can mediate different intracellular mechanisms and thus it is not clear whether therapeutic approaches aimed at targeting this receptor subtype will have beneficial outcomes in HD patients.…”

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

“…Furthermore, caffeine ameliorates the freezing of gait that occurs in Parkinson's disease patients (Kitagawa et al 2007 ) . A number of clinical trials are under way to evaluate the potential of A 2A R antagonists in the treatment of Parkinson's disease (Table 29.2 ), and the modulation of A 1 and A 2A Rs may be effective in the treatment of Huntington's disease as well Chou et al 2005 ;Popoli et al 2007 ) .…”

The A2A Adenosine Receptor Is a Dual Coding Gene

“…The A 2A adenosine receptor (A 2A R), 3 which is encoded by the Adora2a gene, is one of the most well studied G proteincoupled receptors because it is a major target of caffeine and a drug target for several brain disorders (12)(13)(14)(15). Previous studies have shown that A 2A R is widely expressed throughout the body, with the highest level of expression in the striatum (16 -20).…”