Sound preconditioning therapy inhibits ototoxic hearing loss in mice
Soumen Roy, Matthew M. Ryals, Astrid Botty Van den Bruele, Tracy S. Fitzgerald, Lisa L. Cunningham
Soumen Roy, Matthew M. Ryals, Astrid Botty Van den Bruele, Tracy S. Fitzgerald, Lisa L. Cunningham
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Brief Report Otology

Sound preconditioning therapy inhibits ototoxic hearing loss in mice

Abstract

Therapeutic drugs with ototoxic side effects cause significant hearing loss for thousands of patients annually. Two major classes of ototoxic drugs are cisplatin and the aminoglycoside antibiotics, both of which are toxic to mechanosensory hair cells, the receptor cells of the inner ear. A critical need exists for therapies that protect the inner ear without inhibiting the therapeutic efficacy of these drugs. The induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death and hearing loss. We hypothesized that exposure to sound that is titrated to stress the inner ear without causing permanent damage would induce HSPs in the cochlea and inhibit ototoxic drug–induced hearing loss. We developed a sound exposure protocol that induces HSPs without causing permanent hearing loss. We used this protocol in conjunction with a newly developed mouse model of cisplatin ototoxicity and found that preconditioning mouse inner ears with sound has a robust protective effect against cisplatin-induced hearing loss and hair cell death. Sound therapy also provided protection against aminoglycoside-induced hearing loss. These data indicate that sound preconditioning protects against both classes of ototoxic drugs, and they suggest that sound therapy holds promise for preventing hearing loss in patients receiving these drugs.

Authors

Soumen Roy, Matthew M. Ryals, Astrid Botty Van den Bruele, Tracy S. Fitzgerald, Lisa L. Cunningham

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Figure 2

Sound preconditioning protects against cisplatin ototoxicity.

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Sound preconditioning protects against cisplatin ototoxicity. (A) Mouse ...
(A) Mouse model of cisplatin ototoxicity. Mice underwent three cycles of cisplatin administration consisting of 4 mg/kg/day for 4 days (4×4 protocol) or 8 mg/kg/day for 2 days (8×2 protocol) followed by 10 days of recovery. Hearing was tested by ABR before cisplatin administration and 15 days after the final cycle. Cisplatin caused significant permanent threshold shifts across frequencies (ANOVA, *P < 0.05, asterisks indicate significance relative to saline-treated mice. Shown are the means ± SD). (B) Outer hair cell (OHCs) function was examined using DPOAEs. Cisplatin reduced DPOAE amplitudes (ANOVA, *P < 0.05, asterisk denotes significance relative to the saline-treated mice. Shown are the means ± SD). (C) Timeline of cisplatin administration and sound exposures. (D) Mice that received cisplatin alone had significant hearing loss at all frequencies relative to mice that received sound alone or saline alone. Sound preconditioning significantly inhibited cisplatin-induced hearing loss (ANOVA, *P < 0.05, asterisk indicates significance between cisplatin and cisplatin plus sound). (E and F) Cisplatin caused significant loss of OHCs in the upper middle cochlear turn (1.5 mm from the apex) and near-total loss of OHCs in the middle and basal cochlear turns (2.0–3.2 mm from the apex). Sound preconditioning significantly improved OHC survival in the middle and the upper basal turns (ANOVA, *P < 0.05). Scale bar: 20 μm. IHCs, inner hair cells.