title: Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease.
abstract: Minocycline is broadly protective in neurologic disease models featuring cell death and is being evaluated in clinical trials. We previously demonstrated that minocycline-mediated protection against caspase-dependent cell death related to its ability to prevent mitochondrial cytochrome c release. These results do not explain whether or how minocycline protects against caspase-independent cell death. Furthermore, there is no information on whether Smac/Diablo or apoptosis-inducing factor might play a role in chronic neurodegeneration. In a striatal cell model of Huntington's disease and in R6/2 mice, we demonstrate the association of cell death/disease progression with the recruitment of mitochondrial caspase-independent (apoptosis-inducing factor) and caspase-dependent (Smac/Diablo and cytochrome c) triggers. We show that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways. Furthermore, this report demonstrates recruitment of Smac/Diablo and apoptosis-inducing factor in chronic neurodegeneration. Our results further delineate the mechanism by which minocycline mediates its remarkably broad neuroprotective effects.
authors.affiliation: Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.forename: Martin
authors.initials: M
authors.lastname: Drozda
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhang
authors.forename: Irina G
authors.initials: IG
authors.lastname: Stavrovskaya
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
mesh_terms: D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008911:Minocycline / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494815:Bid protein, mouse; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases; D008911:Minocycline