Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice (original) (raw)

• Letter
• Published: 02 May 2002
• Irina G. Stavrovskaya3,
• Martin Drozda1,2,
• Betty Y. S. Kim1,2,
• Victor Ona1,2,
• Mingwei Li1,2,
• Satinder Sarang4,
• Allen S. Liu1,2,
• Dean M. Hartley5,
• Du Chu Wu6,
• Steven Gullans4,
• Robert J. Ferrante8,7,
• Serge Przedborski6,9,
• Bruce S. Kristal3,10 &
• …
• Robert M. Friedlander1,2

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

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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.

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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

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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.).

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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
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2. Irina G. Stavrovskaya
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3. Martin Drozda
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4. Betty Y. S. Kim
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5. Victor Ona
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6. Mingwei Li
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7. Satinder Sarang
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8. Allen S. Liu
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9. Dean M. Hartley
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10. Du Chu Wu
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11. Steven Gullans
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12. Robert J. Ferrante
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13. Serge Przedborski
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14. Bruce S. Kristal
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15. Robert M. Friedlander
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Correspondence toRobert M. Friedlander.

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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

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• Received: 21 February 2002
• Accepted: 05 April 2002
• Issue Date: 02 May 2002
• DOI: https://doi.org/10.1038/417074a

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