期刊
JOURNAL OF NEUROSCIENCE
卷 28, 期 38, 页码 9473-9485出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1867-08.2008
关键词
drug screen; inhibitors of cytochrome c release; methazolamide; Huntington's disease; R6/2 mice; mutant-htt ST14A cells
资金
- National Institutes of Health-National Institute of Neurological Disorders and Stroke
- Huntington's Disease Society of America
- Hereditary Disease Foundation
- New York State Center of Research Excellence
- Veterans Administration
Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria. Drugs effective at the level of purified mitochondria were evaluated in a cellular model of HD. As proof of principle, one drug was chosen for in depth evaluation in vitro and a transgenic mouse model of HD. Our findings demonstrate the utility of mitochondrial screening to identify inhibitors of cell death and provide further support for the important functional role of cytochrome c release in HD. Given that many of these compounds have been approved by the Food and Drug Administration for clinical usage and cross the blood-brain barrier, these drugs may lead to trials in patients.
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