title: Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.
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.
authors.affiliation: Neuroapoptosis Laboratory and Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.forename: Zhijuan
authors.initials: Z
authors.lastname: Pei
authors.forename: Martin
authors.initials: M
authors.lastname: Drozda
authors.forename: Irina G
authors.initials: IG
authors.lastname: Stavrovskaya
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Del Signore
authors.forename: Kerry
authors.initials: K
authors.lastname: Cormier
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shimony
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D045304:Cytochromes c / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008136:Longevity / Q000187:drug effects / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008704:Methazolamide / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D018696:Neuroprotective Agents; D045304:Cytochromes c; D020169:Caspases; D008704:Methazolamide
references.citation: Physiol Genomics. 2002 Oct 29;11(2):45-52
references.pmid: 12388792
references.citation: Cell. 1997 Aug 8;90(3):405-13
references.pmid: 9267021
references.citation: Stroke. 1996 Sep;27(9):1578-85
references.pmid: 8784133
references.citation: J Neurosci. 2000 May 15;20(10):3705-13
references.pmid: 10804212
references.citation: Nature. 2002 May 2;417(6884):74-8
references.pmid: 11986668
references.citation: Biochem Soc Symp. 1999;66:43-54
references.pmid: 10989656
references.citation: Biochim Biophys Acta. 2005 Jul 15;1708(3):375-92
references.pmid: 15979561
references.citation: Nature. 2001 Jul 5;412(6842):95-9
references.pmid: 11452314
references.citation: Neurobiol Dis. 2004 Aug;16(3):546-55
references.pmid: 15262266
references.citation: Ann Neurol. 2003 Dec;54(6):841-2
references.pmid: 14681898
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15769-74
references.pmid: 9861045
references.citation: Biochim Biophys Acta. 2005 Jan 7;1706(1-2):40-52
references.pmid: 15620364
references.citation: Neurobiol Dis. 2005 Nov;20(2):500-8
references.pmid: 15908226
references.citation: Exp Mol Pathol. 1984 Apr;40(2):246-61
references.pmid: 6705894
references.citation: Nature. 1999 May 20;399(6733):263-7
references.pmid: 10353249
references.citation: J Biol Chem. 2008 Jan 11;283(2):665-76
references.pmid: 17962193
references.citation: Int Immunopharmacol. 2001 Nov;1(12):2173-82
references.pmid: 11710546
references.citation: Biochim Biophys Acta. 2006 Aug;1762(8):742-54
references.pmid: 16920334
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9685-90
references.pmid: 16769901
references.citation: Biochim Biophys Acta. 2006 Mar;1762(3):373-80
references.pmid: 16364609
references.citation: J Neurosci Res. 2001 Oct 1;66(1):135-45
references.pmid: 11599010
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13496-500
references.pmid: 10557349
references.citation: Nat Med. 2000 Jul;6(7):797-801
references.pmid: 10888929
references.citation: Neurochem Res. 2004 Nov;29(11):1943-9
references.pmid: 15662830
references.citation: Cell. 1997 Nov 14;91(4):479-89
references.pmid: 9390557
references.citation: Science. 2002 Jul 12;297(5579):259-63
references.pmid: 12114629
references.citation: Cell. 1996 Nov 1;87(3):493-506
references.pmid: 8898202
references.citation: Cell. 2000 Jul 7;102(1):33-42
references.pmid: 10929711
references.citation: Ann Neurol. 2003 Aug;54(2):186-96
references.pmid: 12891671
references.citation: Nature. 2000 Oct 12;407(6805):770-6
references.pmid: 11048727
references.citation: Apoptosis. 2004 Mar;9(2):131-43
references.pmid: 15004510
references.citation: N Engl J Med. 2003 Apr 3;348(14):1365-75
references.pmid: 12672865
references.citation: J Biol Chem. 2001 May 4;276(18):14545-8
references.pmid: 11278258
references.citation: NeuroRx. 2005 Jul;2(3):447-64
references.pmid: 16389308
references.citation: Neurology. 2006 Mar 14;66(5):664-71
references.pmid: 16481597
references.citation: Neurosurgery. 2001 Jun;48(6):1393-9; discussion 1399-401
references.pmid: 11383749
references.citation: J Neurosci. 2001 Apr 15;21(8):2580-8
references.pmid: 11306611
references.citation: Biochem Soc Symp. 1999;66:167-79
references.pmid: 10989666
references.citation: Eur J Biochem. 1999 Sep;264(3):687-701
references.pmid: 10491114
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10483-7
references.pmid: 12930891
references.citation: Stroke. 1992 Nov;23(11):1595-601
references.pmid: 1279842
references.citation: J Neurosci. 2005 Dec 14;25(50):11645-54
references.pmid: 16354923
references.citation: FEBS Lett. 2004 Jun 4;567(2-3):281-6
references.pmid: 15178337
references.citation: Nature. 2005 Jan 6;433(7021):73-7
references.pmid: 15635412
references.citation: J Neurosci. 2002 Mar 1;22(5):1763-71
references.pmid: 11880505
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16012-7
references.pmid: 14663141
references.citation: Brain. 2002 Jun;125(Pt 6):1297-308
references.pmid: 12023318
references.citation: J Exp Med. 2004 Jul 19;200(2):211-22
references.pmid: 15263028
references.citation: Ann Neurol. 2003 Dec;54(6):841; author reply 842-3
references.pmid: 14681897