Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 417, pages 74–78 (2002)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Minocycline delays onset and extends survival in ALS mice.
Figure 2: Minocycline inhibits cell death, caspase activation and cytochrome c release.
Figure 3: Minocycline inhibits cytochrome c release and swelling in purified mitochondria.
Figure 4: Minocycline inhibits cytochrome c release in ALS and ischaemia.

Similar content being viewed by others

References

  1. Yrjanheikki, J., Keinanen, R., Pellikka, M., Hokfelt, T. & Koistinaho, J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc. Natl Acad. Sci. USA 95, 15769–15774 (1998)

    Article  ADS  CAS  Google Scholar 

  2. Chen, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med. 6, 797–801 (2000)

    Article  CAS  Google Scholar 

  3. Sanchez Mejia, R. O., Ona, V. O., Li, M. & Friedlander, R. M. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 48, 1393–1401 (2001)

    Article  CAS  Google Scholar 

  4. Tikka, T., Fiebich, B. L., Goldsteins, G., Keinanen, R. & Koistinaho, J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J. Neurosci. 21, 2580–2588 (2001)

    Article  CAS  Google Scholar 

  5. Wu, D. C. et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22, 1763–1771 (2002)

    Article  CAS  Google Scholar 

  6. Du, Y. et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc. Natl Acad. Sci. USA 98, 14669–14674 (2001)

    Article  ADS  CAS  Google Scholar 

  7. Friedlander, R. M., Brown, R. H., Gagliardini, V., Wang, J. & Yuan, J. Inhibition of ICE slows ALS in mice. Nature 388, 31 (1997)

    Article  ADS  CAS  Google Scholar 

  8. Almer, G., Vukosavic, S., Romero, N. & Przedborski, S. Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. J. Neurochem. 72, 2415–2425 (1999)

    Article  CAS  Google Scholar 

  9. Li, M. et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288, 335–339 (2000)

    Article  ADS  CAS  Google Scholar 

  10. Brogden, R. N., Speight, T. M. & Avery, G. S. Minocycline: A review of its antibacterial and pharmacokinetic properties and therapeutic use. Drugs 9, 251–291 (1975)

    Article  CAS  Google Scholar 

  11. Ona, V. O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263–267 (1999)

    Article  ADS  CAS  Google Scholar 

  12. Rowland, L. P. & Shneider, N. A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 344, 1688–1700 (2001)

    Article  CAS  Google Scholar 

  13. Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993)

    Article  ADS  CAS  Google Scholar 

  14. Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994)

    Article  ADS  CAS  Google Scholar 

  15. Wong, P. C. et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105–1116 (1995)

    Article  CAS  Google Scholar 

  16. Green, D. R. & Reed, J. C. Mitochondria and apoptosis. Science 281, 1309–1312 (1998)

    Article  CAS  Google Scholar 

  17. Li, H., Zhu, H., Xu, C. J. & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501 (1998)

    Article  CAS  Google Scholar 

  18. Luo, X., Budihardjo, I., Zou, H., Slaughter, C. & Wang, X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481–490 (1998)

    Article  CAS  Google Scholar 

  19. Zamzami, N. et al. Bid acts on the permeability transition pore complex to induce apoptosis. Oncogene 19, 6342–6350 (2000)

    Article  CAS  Google Scholar 

  20. Bernardi, P., Scorrano, L., Colonna, R., Petronilli, V. & Di Lisa, F. Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur. J. Biochem. 264, 687–701 (1999)

    Article  CAS  Google Scholar 

  21. Kristal, B. S. & Dubinsky, J. M. Mitochondrial permeability transition in the central nervous system: induction by calcium cycling-dependent and -independent pathways. J. Neurochem. 69, 524–538 (1997)

    Article  CAS  Google Scholar 

  22. Friberg, H., Connern, C., Halestrap, A. P. & Wieloch, T. Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability. J. Neurochem. 72, 2488–2497 (1999)

    Article  CAS  Google Scholar 

  23. Shimizu, S., Narita, M. & Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399, 483–487 (1999)

    Article  ADS  CAS  Google Scholar 

  24. Guegan, C., Vila, M., Rosoklija, G., Hays, A. P. & Przedborski, S. Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis. J. Neurosci. 21, 6569–6576 (2001)

    Article  CAS  Google Scholar 

  25. Hartley, D. M. et al. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19, 8876–8884 (1999)

    Article  CAS  Google Scholar 

  26. Friedlander, R. M. et al. Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J. Exp. Med. 185, 933–940 (1997)

    Article  CAS  Google Scholar 

  27. Kristal, B. S. & Brown, A. M. Apoptogenic ganglioside GD3 directly induces the mitochondrial permeability transition. J. Biol. Chem. 274, 23169–23175 (1999)

    Article  CAS  Google Scholar 

  28. Lai, J. C. & Clark, J. B. Preparation of synaptic and nonsynaptic mitochondria from mammalian brain. Methods Enzymol. 55, 51–60 (1979)

    Article  CAS  Google Scholar 

  29. Kristal, B. S., Staats, P. N. & Shestopalov, A. I. Biochemical characterization of the mitochondrial permeability transition in isolated forebrain mitochondria. Dev. Neurosci. 22, 376–383 (2000)

    Article  CAS  Google Scholar 

  30. Krasnikov, B. F., Kuzminova, A. E. & Zorov, D. B. The Ca2 +-induced pore opening in mitochondria energized by succinate-ferricyanide electron transport. FEBS Lett. 419, 137–140 (1997)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Friedlander for editorial assistance, B. Krasnikov for discussion concerning the 4-channel mitochondrial chamber, and M. Lukyanova for technical assistance. Mouse Bid expression construct was provided by H. Li and J. Yuan. This work was supported by Project A.L.S. (R.M.F., S.G., S.P.), the NIH (R.M.F., D.M.H, R.J.F., S.P., B.S.K.), the Huntington's Disease Society of America (R.M.F.), the Hereditary Disease Foundation (R.M.F., B.S.K.), the Muscular Dystrophy Association (R.M.F., S.P.), the Veterans Administration (R.J.F.), Hope for ALS (S.G.), Ride for ALS (S.G.), ALS Association (S.P.), the US Department of Defense (S.P.), the Lowenstein Foundation (S.P.), the Smart Foundation (S.P.), and the Parkinson's Disease Foundation (S.P.).

Author information

Authors and Affiliations

  1. Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Shan Zhu, Martin Drozda, Betty Y. S. Kim, Victor Ona, Mingwei Li, Allen S. Liu & Robert M. Friedlander

  2. Women's Hospital, Harvard Medical School,

    Shan Zhu, Martin Drozda, Betty Y. S. Kim, Victor Ona, Mingwei Li, Allen S. Liu & Robert M. Friedlander

  3. Burke Medical Research Institute, White Plains, New York, 10605, USA

    Irina G. Stavrovskaya & Bruce S. Kristal

  4. Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Satinder Sarang & Steven Gullans

  5. Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Dean M. Hartley

  6. Department of Neurology, Columbia University, New York, New York, 10032, USA

    Du Chu Wu & Serge Przedborski

  7. Department of Pathology, Columbia University, New York, New York, 10032, USA

    Robert J. Ferrante

  8. Geriatric Research Education and Clinical Center, Bedford VA Medical Center, Bedford, Massachusetts, 01730, USA

    Robert J. Ferrante

  9. Neurology, Pathology, and Psychiatry Departments, Boston University School of Medicine, Boston, Massachusetts, 02118, USA

    Serge Przedborski

  10. Departments of Biochemistry and Neuroscience, Weill Medical College of Cornell University, New York, New York, 10021, USA

    Bruce S. Kristal

Authors
  1. Shan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irina G. Stavrovskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Drozda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Betty Y. S. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Victor Ona
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingwei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satinder Sarang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Allen S. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dean M. Hartley
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Du Chu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Steven Gullans
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robert J. Ferrante
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Serge Przedborski
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Bruce S. Kristal
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Robert M. Friedlander
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert M. Friedlander.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, S., Stavrovskaya, I., Drozda, M. et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417, 74–78 (2002). https://doi.org/10.1038/417074a

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/417074a

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing