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The Journal of Neuroscience, September 17, 2008, 28(38):9473-9485; doi:10.1523/JNEUROSCI.1867-08.2008

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Neurobiology of Disease
Inhibitors of Cytochrome c Release with Therapeutic Potential for Huntington's Disease

Xin Wang,^1 * Shan Zhu,^1 * Zhijuan Pei,¹ Martin Drozda,¹ Irina G. Stavrovskaya,^2,3 Steven J. Del Signore,^4,5,6,7 Kerry Cormier,^4,5,6,7 Ethan M. Shimony,¹ Hongyan Wang,¹ Robert J. Ferrante,^4,5,6,7 Bruce S. Kristal,^2,3,8 and Robert M. Friedlander¹

¹Neuroapoptosis Laboratory and ²Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, ³Dementia Research Service, Burke Medical Research Institute, White Plains, New York 10605, ⁴Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, ⁵Departments of Neurology, ⁶Pathology, and ⁷Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, and ⁸Department of Neuroscience, Cornell University Medical College, New York, New York 10021

Correspondence should be addressed to Dr. Robert M. Friedlander, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, LMRC 123, Boston, MA 02115. Email: rfriedlander{at}rics.bwh.harvard.edu

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.

Key words: drug screen; inhibitors of cytochrome c release; methazolamide; Huntington's disease; R6/2 mice; mutant-htt ST14A cells

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Received April 28, 2008; revised July 24, 2008; accepted Aug. 6, 2008.

Correspondence should be addressed to Dr. Robert M. Friedlander, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, LMRC 123, Boston, MA 02115. Email: rfriedlander{at}rics.bwh.harvard.edu

This article has been cited by other articles:

				X. Wang, B. E. Figueroa, I. G. Stavrovskaya, Y. Zhang, A. C. Sirianni, S. Zhu, A. L. Day, B. S. Kristal, and R. M. Friedlander Methazolamide and Melatonin Inhibit Mitochondrial Cytochrome C Release and Are Neuroprotective in Experimental Models of Ischemic Injury Stroke, May 1, 2009; 40(5): 1877 - 1885. [Abstract] [Full Text] [PDF]

				M. A. King, C. G. Goemans, F. Hafiz, J. H. M. Prehn, A. Wyttenbach, and A. M. Tolkovsky Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons J. Neurosci., December 31, 2008; 28(53): 14401 - 14415. [Abstract] [Full Text] [PDF]

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