Inhibition of caspases alleviates gentamicin-induced cochlear damage in guinea pigs.
The efficacy of caspase inhibitors for protecting the cochlea was evaluated in an in vivo study using guinea pigs, as the animal model system. Gentamicin (12 mg/ml) was delivered via an osmotic pump into the cochlear perilymphatic space of guinea pigs at 0.5 microl/h for 14 days. Additional animals were given either z-Val-Ala-Asp (Ome)-fluoromethyl ketone (z-VAD-FMK) or z-Leu-Glu-His-Asp-FMK (z-LEHD-FMK), a general caspase inhibitor and a caspase 9 inhibitor, respectively, in addition to gentamicin. The elevation in auditory brain stem response thresholds, at 4, 7, and 14 days following gentamicin administration, were decreased in animals that received both z-VAD-FMK and z-LEHD-FMK. Cochlear sensory hair cells survived in greater numbers in animals that received caspase inhibitors in addition to gentamicin, whereas sensory hair cells in animals that received gentamicin only were severely damaged. These results suggest that auditory cell death induced by gentamicin is closely related to the activation of caspases in vivo.
Okuda
Takeshi
T
Department of Otolaryngology, Yamaguchi University School of Medicine, Minamikogushi 1-1-1, Ube, Yamaguchi, Japan.
Sugahara
Kazuma
K
Takemoto
Tsuyoshi
T
Shimogori
Hiroaki
H
Yamashita
Hiroshi
H
D000287:Administration, Topical; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000617:Aminoglycosides / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D001309:Auditory Threshold / Q000502:physiology; D061945:Caspase Inhibitors; D015834:Cochlear Diseases / Q000139:chemically induced*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005839:Gentamicins / Q000008:administration & dosage / Q000009:adverse effects*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010498:Perilymph / Q000187:drug effects
D000590:Amino Acid Chloromethyl Ketones; D000617:Aminoglycosides; D061945:Caspase Inhibitors; D005839:Gentamicins; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone