Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo.
The sensory hair cells of the inner ear undergo apoptosis after acoustic trauma or aminoglycoside antibiotic treatment, causing permanent auditory and vestibular deficits in humans. Previous studies have demonstrated a role for caspase activation in hair cell death and ototoxic injury that can be reduced by concurrent treatment with caspase inhibitors in vitro. In this study, we examined the protective effects of caspase inhibition on hair cell death in vivo after systemic injections of aminoglycosides. In one series of experiments, chickens were implanted with osmotic pumps that administrated the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethylketone (zVAD) into inner ear fluids. One day after the surgery, the animals received a 5 d course of treatment with streptomycin, a vestibulotoxic aminoglycoside. Direct infusion of zVAD into the vestibule significantly increased hair cell survival after streptomycin treatment. A second series of experiments determined whether rescued hair cells could function as sensory receptors. Animals treated with streptomycin displayed vestibular system impairment as measured by a greatly reduced vestibulo-ocular response (VOR). In contrast, animals that received concurrent systemic administration of zVAD with streptomycin had both significantly greater hair cell survival and significantly increased VOR responses, as compared with animals treated with streptomycin alone. These findings suggest that inhibiting the activation of caspases promotes the survival of hair cells and protects against vestibular function deficits after aminoglycoside treatment.
Matsui
Jonathan I
JI
Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri 63110, USA.
Haque
Asim
A
Huss
David
D
Messana
Elizabeth P
EP
Alosi
Julie A
JA
Roberson
David W
DW
Cotanche
Douglas A
DA
Dickman
J David
JD
Warchol
Mark E
ME
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064032:Calbindin 2; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004333:Drug Administration Routes; D005133:Eye Movements / Q000187:drug effects; D018069:Hair Cells, Vestibular / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015918:Infusion Pumps, Implantable; D010775:Photic Stimulation; D012027:Reflex, Vestibulo-Ocular / Q000187:drug effects; D012399:Rotation; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis; D012444:Saccule and Utricle / Q000187:drug effects / Q000648:ultrastructure; D013307:Streptomycin / Q000633:toxicity
D000590:Amino Acid Chloromethyl Ketones; D000617:Aminoglycosides; D064032:Calbindin 2; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D064030:S100 Calcium Binding Protein G; C476093:z-Val-Ala-Asp(Ome)-fluoromethylketone; D013307:Streptomycin