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

• Published in: Nature (London) Vol. 417; no. 6884; pp. 74 - 78
• Main Authors: Friedlander, Robert M, Zhu, Shan, Stavrovskaya, Irina G, Drozda, Martin, Kim, Betty Y. S, Ona, Victor, Li, Mingwei, Sarang, Satinder, Liu, Allen S, Hartley, Dean M, Wu, Du Chu, Gullans, Steven, Ferrante, Robert J, Przedborski, Serge, Kristal, Bruce S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 02.05.2002; Nature Publishing Group
• Subjects: Age of Onset; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Biological and medical sciences; Caspases - metabolism; Cell Death - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cytochrome; Cytochrome c Group - metabolism; Disease Progression; Drug therapy; Enzyme Activation - drug effects; Humans; Infarction, Middle Cerebral Artery; Ischemia - metabolism; Ischemia - pathology; Medical disorders; Medical sciences; Mice; Mice, Inbred C57BL; Minocycline - pharmacology; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondrial Swelling - drug effects; N-Methylaspartate - toxicity; Neurology; Neuropharmacology; Neuroprotective agent; Nitric oxide; Permeability - drug effects; Pharmacology. Drug treatments; Rats; Rodents; Survival Rate; Tumor Cells, Cultured; Nervous system diseases; Tetracycline derivatives; Rodentia; Amyotrophic lateral sclerosis; Neuroprotective agent; Cytochrome c; Vertebrata; Antibiotic; Chemotherapy; Mitochondria; Mammalia; Treatment; Mouse; Animal; Central nervous system disease; Minocycline; Degenerative disease; Mechanism of action; Spinal cord disease
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/417074a

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.