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

被引：66

作者：

Huang, Nai-Kuei ^{[1
]}

Lin, Jung-Hsin ^{[2
,3
]}

Lin, Jiun-Tsai ^{[3
]}

Lin, Chia-I ^{[5
]}

Liu, Eric Minwei ^{[4
]}

Lin, Chun-Jung ^{[4
]}

Chen, Wan-Ping ^{[1
]}

Shen, Yuh-Chiang ^{[1
]}

Chen, Hui-Mei ^{[3
]}

Chen, Jhih-Bin ^{[5
]}

Lai, Hsing-Lin ^{[3
]}

Yang, Chieh-Wen ^{[5
]}

Chiang, Ming-Chang ^{[7
]}

Wu, Yu-Shuo ^{[3
]}

Chang, Chen ^{[3
]}

Chen, Jiang-Fan ^{[8
]}

Fang, Jim-Min ^{[5
,6
]}

Lin, Yun-Lian ^{[1
]}

Chern, Yijuang ^{[3
]}

机构：

[1] Natl Res Inst Chinese Med, Taipei, Taiwan

[2] Acad Sinica, Div Mech, Res Ctr Appl Sci, Taipei 115, Taiwan

[3] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan

[4] Natl Taiwan Univ, Sch Pharm, Taipei 10764, Taiwan

[5] Natl Taiwan Univ, Dept Chem, Taipei 10764, Taiwan

[6] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan

[7] Chinese Culture Univ, Grad Inst Biotechnol, Taipei, Taiwan

[8] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

来源：

PLOS ONE | 2011年 / 6卷 / 06期

关键词：

RAT PHEOCHROMOCYTOMA CELLS; SITE-DIRECTED MUTAGENESIS; UREA CYCLE DEFICIENCY; A(2A) RECEPTOR; MOUSE MODEL; SERUM DEPRIVATION; STRUCTURE PREDICTION; MUTANT HUNTINGTIN; CRYSTAL-STRUCTURE; STRIATAL LESIONS;

D O I：

10.1371/journal.pone.0020934

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: Huntington'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 Findings: Here, we report a novel dual-function compound, N-6-(4-hydroxybenzyl) adenine riboside (designated T1-11) which activates the A(2A)R 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 A(2A)R 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 A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R 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/Significance: The 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.

引用

页数：13