Wnt Signaling Protects against Paclitaxel-Induced Spiral Ganglion Neuron Damage in the Mouse Cochlea In Vitro.

Xue Wang,Man Wang,Zhenbiao Zhang,Haibo Wang,Lei Xu,Yuechen Han,Wenwen Liu,Chuan Bo

doi:10.1155/2019/7878906

Abstract

It has been reported that paclitaxel administration could cause sensorineural hearing loss, and Wnt activation is important for the development and cell protection of mouse cochlea. However, the effect of Wnt signaling in spiral ganglion neurons (SGNs) damage induced by paclitaxel has not yet been elucidated. In this study, we explored the effect of paclitaxel on SGNs in the mouse cochlea and the neuroprotective effects of Wnt signaling pathway against paclitaxel-induced SGN damage by using Wnt agonist/antagonists in vitro. We first found that paclitaxel treatment resulted in a degenerative change and reduction of cell numbers in SGNs and induced caspase-mediated apoptosis in SGNs. The expression levels of β-catenin and C-myc were increased, thus indicating Wnt signaling was activated in SGNs after paclitaxel treatment. The activation of Wnt signaling pathway protected against SGN loss after exposure to paclitaxel, whereas the suppression of Wnt signaling in SGNs made them more vulnerable to paclitaxel treatment. We also showed that activation of Wnt signaling in SGNs inhibited caspase-mediated apoptosis. Our findings demonstrated that Wnt signaling had an important role in protecting SGNs against paclitaxel-induced damage and thus might be an effective therapeutic target for the prevention of paclitaxel-induced SGN death.

Highlights

Paclitaxel, a diterpene plant product isolated from the Taxus chinensis, is an effective antineoplastic agent with antimicrotubule properties
To examine the neurotoxic effect of paclitaxel on spiral ganglion neurons (SGNs), the cochlea middle turn explants isolated from Postnatal 3-day-old (P3) C57BL/6 mice were treated with different concentrations of paclitaxel (10, 20, and 30 μM) for 48 h, respectively (Figure 1(a)), and results showed that three concentrations of paclitaxel inhibited the survival of SGNs to varying degrees compared with the control group
The majority of auditory nerve fibers (ANFs) were fragmented and the peripheral fiber ends approaching hair cell (HC) were almost completely lost in the 30 μM paclitaxel-treated group. ese results indicated that paclitaxel led to a degenerative change and reduction of SGNs in a dose-dependent manner

Summary

Introduction

Paclitaxel, a diterpene plant product isolated from the Taxus chinensis, is an effective antineoplastic agent with antimicrotubule properties. Unlike other antimicrotubule agents that induce microtubule disassembly, paclitaxel shifts the equilibrium towards microtubule assembly which is excessively stable, thereby inhibiting the dynamic reorganization of the microtubule network [1]. Paclitaxel is widely used both alone and in combination with other chemotherapeutic agents for the treatment of various carcinomas including ovarian, breast, lung, and cervical cancers as well as many head and neck neoplasms [2, 3]. Like many other antineoplastic agents, paclitaxel exhibits many side effects of which neutropenia and peripheral neuropathy are the major dose-limiting ones [4, 5]. Data about the effects of paclitaxel on the inner ear are very limited despite that some antineoplastic drugs have been shown to be ototoxic [6]. There have been a few publications presented a relationship between hearing loss and paclitaxel administration [7, 8], but the effect of paclitaxel on SGNs in the mouse cochlea has not yet been fully elucidated

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Conclusion