Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice.
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.
Zhu
Shan
S
Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Stavrovskaya
Irina G
IG
Drozda
Martin
M
Kim
Betty Y S
BY
Ona
Victor
V
Li
Mingwei
M
Sarang
Satinder
S
Liu
Allen S
AS
Hartley
Dean M
DM
Wu
Du Chu
DC
Gullans
Steven
S
Ferrante
Robert J
RJ
Przedborski
Serge
S
Kristal
Bruce S
BS
Friedlander
Robert M
RM
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D016202:N-Methylaspartate / Q000633:toxicity; D010539:Permeability / Q000187:drug effects; D051381:Rats; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D003574:Cytochrome c Group; D016202:N-Methylaspartate; D020169:Caspases; D008911:Minocycline