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Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2008 Sep 17; Vol. 28 (38), pp. 9473-85. - Publication Year :
- 2008
-
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.
- Subjects :
- Animals
Brain metabolism
Brain physiopathology
Carbonic Anhydrase Inhibitors pharmacology
Carbonic Anhydrase Inhibitors therapeutic use
Caspases drug effects
Caspases metabolism
Cell Death drug effects
Cell Death physiology
Cell Line, Transformed
Cytochromes c metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
Huntington Disease metabolism
Huntington Disease physiopathology
Longevity drug effects
Longevity physiology
Membrane Potential, Mitochondrial drug effects
Membrane Potential, Mitochondrial physiology
Methazolamide pharmacology
Methazolamide therapeutic use
Mice
Mice, Transgenic
Mitochondria metabolism
Neuroprotective Agents therapeutic use
Treatment Outcome
Brain drug effects
Cytochromes c antagonists & inhibitors
Huntington Disease drug therapy
Mitochondria drug effects
Neuroprotective Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 28
- Issue :
- 38
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 18799679
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1867-08.2008