Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / drug effects*
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Brain / metabolism
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Brain / physiopathology
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Carbonic Anhydrase Inhibitors / pharmacology
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Carbonic Anhydrase Inhibitors / therapeutic use
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Caspases / drug effects
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Caspases / metabolism
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Cell Death / drug effects
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Cell Death / physiology
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Cell Line, Transformed
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Cytochromes c / antagonists & inhibitors*
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Cytochromes c / metabolism
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Huntington Disease / drug therapy*
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Huntington Disease / metabolism
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Huntington Disease / physiopathology
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Longevity / drug effects
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Longevity / physiology
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / physiology
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Methazolamide / pharmacology
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Methazolamide / therapeutic use
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Mice
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Mice, Transgenic
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Treatment Outcome
Substances
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Carbonic Anhydrase Inhibitors
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Neuroprotective Agents
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Cytochromes c
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Caspases
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Methazolamide