Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice

Shan Zhu, Irina G. Stavrovskaya, Martin Drozda, Betty Y. S. Kim, Victor Ona, Mingwei Li, Satinder Sarang, Allen S. Liu, Dean M. Hartley, Du Chu Wu, Steven Gullans, Robert J. Ferrante, Serge Przedborski, Bruce S. Kristal and Robert M. Friedlander ()
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Shan Zhu: Brigham & Women's Hospital, Harvard Medical School
Irina G. Stavrovskaya: Burke Medical Research Institute
Martin Drozda: Brigham & Women's Hospital, Harvard Medical School
Betty Y. S. Kim: Brigham & Women's Hospital, Harvard Medical School
Victor Ona: Brigham & Women's Hospital, Harvard Medical School
Mingwei Li: Brigham & Women's Hospital, Harvard Medical School
Satinder Sarang: Brigham & Women's Hospital, Harvard Medical School
Allen S. Liu: Brigham & Women's Hospital, Harvard Medical School
Dean M. Hartley: Brigham & Women's Hospital, Harvard Medical School
Du Chu Wu: Columbia University
Steven Gullans: Brigham & Women's Hospital, Harvard Medical School
Robert J. Ferrante: Columbia University
Serge Przedborski: Columbia University
Bruce S. Kristal: Burke Medical Research Institute
Robert M. Friedlander: Brigham & Women's Hospital, Harvard Medical School

Nature, 2002, vol. 417, issue 6884, 74-78

Abstract: Abstract Minocycline mediates neuroprotection in experimental models of neurodegeneration. It inhibits the activity1,2,3,4,5,6 of caspase-1, caspase-3, inducible form of nitric oxide synthetase (iNOS) and p38 mitogen-activated protein kinase (MAPK). Although minocycline does not directly inhibit these enzymes, the effects may result from interference with upstream mechanisms resulting in their secondary activation. Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with ALS7,8,9. Here we report that minocycline delays disease onset and extends survival in ALS mice. Given the broad efficacy of minocycline, understanding its mechanisms of action is of great importance. We find that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release. Minocycline-mediated inhibition of cytochrome c release is demonstrated in vivo, in cells, and in isolated mitochondria. Understanding the mechanism of action of minocycline will assist in the development and testing of more powerful and effective analogues. Because of the safety record of minocycline, and its ability to penetrate the blood–brain barrier, this drug may be a novel therapy for ALS10.

Date: 2002
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DOI: 10.1038/417074a

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