A New Drug Design Targeting the Adenosinergic System for Huntington's Disease

Abstract

BackgroundHuntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed.Methodology/Principal FindingsHere, we report a novel dual-function compound, N 6-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A2AR and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD.Conclusions/SignificanceThe dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

“…Thus, CGS rescues the corticostriatal synaptic disconnection and progressive motor impairment observed in HD mice (15,50). These findings together with several earlier reports suggest that activation of the A 2A R, a cAMP-elevating receptor, is a therapeutic option in HD and elicits beneficial effects on several key HD symptoms (including formation of intranuclear inclusions, impaired motor coordination, brain atrophy, and urea cycle deficiency) (15,(52)(53)(54). Consistent with the possible beneficial role of the A 2A R in HD, Mievis and colleagues demonstrated that elimination of the A 2A R exacerbated HD progression in a mouse model of HD (55).…”

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease

“…Collectively, these findings predict that ENT1 could constitute a new therapeutic target and ENT1 blockers, such as dipyridamole and T1–11 (Huang et al, 2011), could at least delay the age of onset of HD.…”

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…Mice chronically treated with CGS21680 had reduced mHtt aggregate accumulation and had lowered enhancing proteasome activity, while the administration of T1-11 in R6/2 mice enhanced the performance on the rota-rod test, and enhanced proteasome activity. 36,120,153,63,[222][223][224][225] Interestingly, the blockade of A 2A R also has beneficial effects in R6/2 mice. Studies showed that the administration of the A 2A R antagonist SCH58261 in R6/2 mice reduced glutamate and adenosine outflow, normalized the alteration in emotional response, and reduced NMDAinduced toxicity, 226,227 but had no effect on locomotor capability.…”