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Abstract
Calpains, a family of calcium-activated proteases that breakdown proteins, kinases,
phosphatases and transcription factors, can promote cell death. Since leupeptin, a
calpain inhibitor, protected against hair cell loss from acoustic overstimulation,
we hypothesized that it might protect cochlear and vestibular hair cells against gentamicin
(GM) ototoxicity. To test this hypothesis, mouse organotypic cultures from the cochlea,
maculae of the utricle and the crista of the semicircular canal (P1-P3) were treated
with different doses of GM (0.1-3 mM) alone or in the presence of leupeptin (0.1-3
mM). The percentage of outer hair cells (OHCs) and inner hair cells (IHCs) decreased
with increasing doses of GM between 0.1 and 3 mM. The addition of 1 mM of leupeptin
significantly reduced GM-induced damage to IHCs and OHCs; this protective effect was
dose-dependent. GM also significantly reduced hair cell density in the crista and
utricle in a dose-dependent manner between 0.1 and 3 mM. The addition of 1 mM of leupeptin
significantly reduced hair cell loss in the crista and utricle for GM concentrations
between 0.1 and 3 mM. These results suggest that one of the early steps in GM ototoxicity
may involve calcium-activated proteases that lead to the demise of cochlear and vestibular
hair cells.