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

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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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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.

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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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Correspondence to Robert M. Friedlander.

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