title: Caspase-independent pathways of hair cell death induced by kanamycin in vivo.
abstract: Cochlear and vestibular sensory cells undergo apoptosis when exposed to aminoglycoside antibiotics in organ culture, but mechanisms of chronic drug-induced hair cell loss in vivo are unclear. We investigated cell death pathways in a mouse model of progressive kanamycin-induced hair cell loss. Hair cell nuclei showed both apoptotic- and necrotic-like appearances but markers for classic apoptotic pathways (cytochrome c, caspase-9, caspase-3, JNK, TUNEL) were absent. In contrast, drug treatment caused EndoG translocation, activation of mu-calpain, and both the synthesis and activation of cathepsin D. Poly (ADP-ribose) polymerase 1 (PARP1) was decreased, but a caspase-derived 89 kDa PARP1 fragment was not present. The mRNA level of PARP1 remained unchanged. Thus, chronic administration of aminoglycosides causes multiple forms of cell death, without a major contribution by classic apoptosis. These results provide a better understanding of the toxic effects of aminoglycosides and are relevant to design protection from aminoglycoside-induced hearing loss.
authors: Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI 48109-0506, USA.
authors: H
authors: H
authors: Jiang
authors: S-H
authors: SH
authors: Sha
authors: A
authors: A
authors: Forge
authors: J
authors: J
authors: Schacht
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D003051:Cochlea / Q000187:drug effects / Q000473:pathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology; D007612:Kanamycin / Q000633:toxicity*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D009925:Organ of Corti / Q000187:drug effects / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D012333:RNA, Messenger; D007612:Kanamycin; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; D020169:Caspases; C449002:mu-calpain; D002402:Cathepsin D