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

Shan Zhu, Irina G. Stavrovskaya, Martin Drozda, Y S Betty Kim, Victor Ona, Mingwel Li, Satinder Sarang, Allen S. Liu, Dean M. Hartley, Du Chu Wu, Steven Guilans, Robert J. Ferrante, Serge Przedborski, Bruce S. Kristal, Robert M. Friedlander

Research output: Contribution to journalArticle

909 Citations (Scopus)

Abstract

Minocycline mediates neuroprotection in experimental models of neurodegeneration. It inhibits the activity 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 ALS. 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 ALS.

Original languageEnglish (US)
Pages (from-to)74-78
Number of pages5
JournalNature
Volume417
Issue number6884
DOIs
StatePublished - May 2 2002
Externally publishedYes

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Minocycline
Amyotrophic Lateral Sclerosis
Cytochromes c
Caspase 1
p38 Mitogen-Activated Protein Kinases
Blood-Brain Barrier
Nitric Oxide Synthase
Caspase 3
Permeability
Mitochondria
Theoretical Models
Safety

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Zhu, S., Stavrovskaya, I. G., Drozda, M., Kim, Y. S. B., Ona, V., Li, M., ... Friedlander, R. M. (2002). Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature, 417(6884), 74-78. https://doi.org/10.1038/417074a

Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. / Zhu, Shan; Stavrovskaya, Irina G.; Drozda, Martin; Kim, Y S Betty; Ona, Victor; Li, Mingwel; Sarang, Satinder; Liu, Allen S.; Hartley, Dean M.; Wu, Du Chu; Guilans, Steven; Ferrante, Robert J.; Przedborski, Serge; Kristal, Bruce S.; Friedlander, Robert M.

In: Nature, Vol. 417, No. 6884, 02.05.2002, p. 74-78.

Research output: Contribution to journalArticle

Zhu, S, Stavrovskaya, IG, Drozda, M, Kim, YSB, Ona, V, Li, M, Sarang, S, Liu, AS, Hartley, DM, Wu, DC, Guilans, S, Ferrante, RJ, Przedborski, S, Kristal, BS & Friedlander, RM 2002, 'Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice', Nature, vol. 417, no. 6884, pp. 74-78. https://doi.org/10.1038/417074a
Zhu, Shan ; Stavrovskaya, Irina G. ; Drozda, Martin ; Kim, Y S Betty ; Ona, Victor ; Li, Mingwel ; Sarang, Satinder ; Liu, Allen S. ; Hartley, Dean M. ; Wu, Du Chu ; Guilans, Steven ; Ferrante, Robert J. ; Przedborski, Serge ; Kristal, Bruce S. ; Friedlander, Robert M. / Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. In: Nature. 2002 ; Vol. 417, No. 6884. pp. 74-78.
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