Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease

被引:41
|
作者
Masuda, Naoki [1 ]
Peng, Qi [1 ]
Li, Qing [1 ]
Jiang, Mai [1 ]
Liang, Yideng [1 ]
Wang, Xiaofang [1 ]
Zhao, Ming
Wang, Wenfei [1 ]
Ross, Christopher A. [1 ,2 ,3 ]
Duan, Wenzhen [1 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Neurobiol, Baltimore, MD 21287 USA
[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA
关键词
Huntington's disease; tiagabine; neuroprotection; transgenic mouse model; preclinical trials;
D O I
10.1016/j.nbd.2008.01.014
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, incoordination, and shortened life-span, and by huntingtin inclusions and neurodegeneration. We previously screened the 1040 FDA-approved compounds from the NINDS compound library and found that a compound, nipecotic acid, significantly reduced mutant huntingtin aggregations and blocked cell toxicity in an inducible cell model of HD. Because nipecotic acid does not cross the blood-brain barrier (BBB), we studied its analogue, tiagabine, which is able to cross the BBB, in both N171-82Q and R6/2 transgenic mouse models of HD. Tiagabine was administered intraperitoneally at 2 and 5 mg/kg daily in HD mice. We found that tiagabine extended survival, improved motor performance, and attenuated brain atrophy and neurodegencration in N171-82Q HD mice. These beneficial effects were further confirmed in R6/2 HD mice. The levels of tiagabine at effective doses in mouse serum are comparable to the levels in human patients treated with tiagabine. These results suggest that tiagabine may have beneficial effects in the treatment of HD. Because tiagabine is an FDA-approved drug, it may be a promising candidate for future clinical trials for the treatment of HD. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:293 / 302
页数:10
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