Regenerative Effect of a ROCK Inhibitor, Y-27632, on Excitotoxic Trauma in an Organotypic Culture of the Cochlea.

Yutaka Koizumi,Seiji Kakehata,Tsukasa Ito,Kunio Mizutari

doi:10.3389/fncel.2020.572434

Abstract

In the past, most inner ear diseases were thought to start with the impairment of the sensory epithelium of the cochlea before subsequently progressing to secondary neural degeneration. However, recent studies show that loss of primary synapses accompanied by excitotoxic degeneration of peripheral axons is likely to be the underlying pathology in sensorineural hearing loss. Rho-associated coiled-coil containing protein kinase (ROCK) inhibition has been reported to have neuroprotective and regenerative effects on synaptic pathways. Therefore, we analyzed the effect of ROCK inhibition using Y-27632 in a model of peripheral axonal damage in the spiral ganglion neurons created using the glutamate agonists, N-methyl-D-aspartate (NMDA) and kainic acid, to induce excitotoxic trauma in the explanted cochlea. The number of axons projecting to hair cells in the cochlea treated with Y-27632 was significantly greater than those in the cochlea treated only with NMDA + kainic acid. Furthermore, there was a significant increase in synapses between the spiral ganglion and the inner hair cells in the cochlea treated with Y-27632. The findings of this study suggest that ROCK inhibition could be a potential strategy for the regeneration of peripheral axons in the spiral ganglion and synapse formation in the inner hair cells of a cochlea that has sustained excitotoxic injury, which is one of the primary etiologies of inner ear disease.

Highlights

The etiology of sensorineural hearing loss (SNHL) involves two main mechanisms, the loss of sensory epithelium and/or the loss of sensory neurons (Wang et al, 2002; Sugawara et al, 2005; Liberman and Kujawa, 2017)
QPCR analysis revealed that mRNA expression levels of RhoA, ROCK1, and ROCK2 were increased (Figure 2)
We found that mRNA expression levels of RhoA, ROCK1, and ROCK2 were increased in NMDA and kainite (NK)-treated cochlea

Summary

Introduction

The etiology of sensorineural hearing loss (SNHL) involves two main mechanisms, the loss of sensory epithelium and/or the loss of sensory neurons (Wang et al, 2002; Sugawara et al, 2005; Liberman and Kujawa, 2017). The sensory epithelium, which includes hair cells and supporting cells, is the primary receptor of sound. Spiral ganglion neurons (SGNs) form synaptic connections with hair cells, which receive sound signals, convert them into action potentials, and convey them to the auditory center via SGNs. The conventional thinking has been that inner ear disease begins with impairment of the sensory epithelium of the cochlea and is followed by secondary neural degeneration (Johnsson, 1974; Bohne and Harding, 2000). Primary neural degeneration of the cochlea without loss of hair cells is considered to be a rare cause of SNHL. Recent studies have shown that primary synapse degeneration, known as cochlear neuropathy, which

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Conclusion