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Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea.

ABSTRACT: Recent studies have reported the role of Wnt/β-catenin signaling in hair cell (HC) development, regeneration, and differentiation in the mouse cochlea; however, the role of Wnt/β-catenin signaling in HC protection remains unknown. In this study, we took advantage of transgenic mice to specifically knockout or overactivate the canonical Wnt signaling mediator β-catenin in HCs, which allowed us to investigate the role of Wnt/β-catenin signaling in protecting HCs against neomycin-induced damage. We first showed that loss of β-catenin in HCs made them more vulnerable to neomycin-induced injury, while constitutive activation of β-catenin in HCs reduced HC loss both in vivo and in vitro. We then showed that loss of β-catenin in HCs increased caspase-mediated apoptosis induced by neomycin injury, while β-catenin overexpression inhibited caspase-mediated apoptosis. Finally, we demonstrated that loss of β-catenin in HCs led to increased expression of forkhead box O3 transcription factor (Foxo3) and Bim along with decreased expression of antioxidant enzymes; thus, there were increased levels of reactive oxygen species (ROS) after neomycin treatment that might be responsible for the increased aminoglycoside sensitivity of HCs. In contrast, β-catenin overexpression reduced Foxo3 and Bim expression and ROS levels, suggesting that β-catenin is protective against neomycin-induced HC loss. Our findings demonstrate that Wnt/β-catenin signaling has an important role in protecting HCs against neomycin-induced HC loss and thus might be a new therapeutic target for the prevention of HC death.

SUBMITTER: Liu L

PROVIDER: S-EPMC4823936 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Autophagy protects auditory hair cells against neomycin-induced damage.

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Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage.

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Project description:Aminoglycoside-induced cochlear ototoxicity causes hair cell (HC) loss and results in hearing impairment in patients. Previous studies have developed the concept of an ototoxicity-sensitive period during which the cochleae of young mice are more vulnerable to auditory trauma than adults. Here, we compared neomycin-induced ototoxicity at the following four developmental ages in mice: postnatal day (P)1-P7, P8-P14, P15-P21, and P60-P66. We found that when neomycin was administered between P8 and P14, the auditory brainstem response threshold increase was significantly higher at low frequencies and HC loss was significantly greater in the apical turn of the cochlea compared to neomycin administration during the other age ranges. Quantitative real-time PCR (qPCR) data revealed that the expression of apoptotic markers, including Casp3 and Casp9, was significantly higher when neomycin was injected from P8 to P14, while the expression of the X-linked inhibitor of apoptosis protein (XIAP) gene was significantly higher when neomycin was injected from P60 to P66. Because XIAP expression was low during the neomycin-sensitive period, we overexpressed XIAP in mice and found that it could protect against neomycin-induced hearing loss at low frequencies and HC loss in the apical turn of the cochlea. Altogether, our findings demonstrate a protective role for XIAP against neomycin-induced hearing loss and HC loss in the apical turn of the cochlea during the ototoxic-sensitive period, and suggest that apoptotic factors mediate the effect of neomycin during the ototoxic-sensitive period.

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The Ganglioside Monosialotetrahexosylganglioside Protects Auditory Hair Cells Against Neomycin-Induced Cytotoxicity Through Mitochondrial Antioxidation: An <i>in vitro</i> Study.

Project description:Neomycin is a common ototoxic aminoglycoside antibiotic that causes sensory hearing disorders worldwide, and monosialotetrahexosylganglioside (GM1) is reported to have antioxidant effects that protect various cells. However, little is known about the effect of GM1 on neomycin-induced hair cell (HC) ototoxic damage and related mechanism. In this study, cochlear HC-like HEI-OC-1 cells along with whole-organ explant cultures were used to establish an in vitro neomycin-induced HC damage model, and then the apoptosis rate, the balance of oxidative and antioxidant gene expression, reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were measured. GM1 could maintain the balance of oxidative and antioxidant gene expression, inhibit the accumulation of ROS and proapoptotic gene expression, promoted antioxidant gene expression, and reduce apoptosis after neomycin exposure in HEI-OC-1 cells and cultured cochlear HCs. These results suggested that GM1 could reduce ROS aggregation, maintain mitochondrial function, and improve HC viability in the presence of neomycin, possibly through mitochondrial antioxidation. Hence, GM1 may have potential clinical value in protecting against aminoglycoside-induced HC injury.

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Pitavastatin protects against neomycin-induced ototoxicity through inhibition of endoplasmic reticulum stress.

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| S-EPMC9381809 | biostudies-literature

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