|Title:||A new drug design targeting the adenosinergic system for huntington's disease||Authors:||Huang N.-K.
|Issue Date:||2011||Journal Volume:||6||Journal Issue:||6||Start page/Pages:||e20934||Source:||PLoS ONE||Abstract:||
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, N6-(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/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. ? 2011 Huang et al.
|ISSN:||19326203||DOI:||10.1371/journal.pone.0020934||SDG/Keyword:||adenosine; adenosine A1 receptor; adenosine A2 receptor; adenosine A2a receptor; adenosine A2b receptor; brain derived neurotrophic factor; n6 (4 hydroxybenzyl)adenine riboside; protein inhibitor; t 1 11; unclassified drug; adenosine; adenosine A2a receptor; drug derivative; equilibrative nucleoside transporter 1; herbaceous agent; N6 (4 hydroxybenzyl)adenine riboside; N6-(4-hydroxybenzyl)adenine riboside; peptide; plant extract; polyglutamine; SLC29A1 protein, mouse; apoptosis; article; binding affinity; binding site; drug binding; drug design; drug efficacy; drug protein binding; drug purification; drug safety; drug structure; drug targeting; drug uptake; human; Huntington chorea; in vivo study; microdialysis; molecular model; motor coordination; protein aggregation; protein analysis; protein function; treatment duration; animal; cell strain; chemical structure; chemistry; disease model; drug antagonism; drug design; drug effect; female; genetics; male; metabolism; mouse; mouse mutant; pathophysiology; rat; trinucleotide repeat; Mus; Mus musculus; Adenosine; Animals; Disease Models, Animal; Drug Design; Drugs, Chinese Herbal; Equilibrative Nucleoside Transporter 1; Female; Humans; Huntington Disease; Male; Mice; Mice, Knockout; Models, Molecular; PC12 Cells; Peptides; Plant Extracts; Rats; Receptor, Adenosine A2A; Trinucleotide Repeat Expansion
|Appears in Collections:||藥學系|
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