Abstract
Recently, a pathological condition called cochlear synaptopathy has been clarified, and as a disorder of the auditory nerve synapses that occurs prior to failure of hair cells, it has been recognized as a major cause of sensorineural hearing loss. However, cochlear synaptopathy is untreatable. Inhibition of rho-associated coiled-coil containing protein kinase (ROCK), a serine-threonine protein kinase, has been reported to have neuroprotective and regenerative effects on synaptic pathways in the nervous system, including those in the inner ear. We previously demonstrated the regenerative effect of the ROCK inhibitor, Y-27632, on an excitotoxic cochlear nerve damage model in vitro. In this study, we aimed to validate the effect of ROCK inhibition on mice with cochlear synaptopathy induced by laser-induced shock wave (LISW) in vivo. After the elevation of ROCK1/2 expression in the damaged cochlea was confirmed, we administered Y-27632 locally via the middle ear. The amplitude of wave I in the auditory brainstem response and the number of synapses in the Y-27632-treated cochlea increased significantly. These results clearly demonstrate that ROCK inhibition has a promising clinical application in the treatment of cochlear synaptopathy, which is the major pathology of sensorineural hearing loss.
Highlights
Primary cochlear neural degeneration, which is called cochlear synaptopathy, is recognized as a common pathology associated with sensorineural hearing loss [1], which is caused by various etiologies, such as noise [2], aging [3], congenital genetic factors [4], and blast exposure [5]
We examined the effects of Ras homolog (Rho)-associated coiled-coil containing protein kinase (ROCK) inhibitors on the damaged synapse between inner hair cell (IHC) and the auditory nerve using a cochlear synaptopathy model generated by a laser-induced shock wave (LISW)
ROCK1 was expressed around the outer hair cell area; no expression was observed around the IHC area (Fig. 1a, a’, a”)
Summary
Primary cochlear neural degeneration, which is called cochlear synaptopathy, is recognized as a common pathology associated with sensorineural hearing loss [1], which is caused by various etiologies, such as noise [2], aging [3], congenital genetic factors [4], and blast exposure [5]. We examined the effects of ROCK inhibitors on the damaged auditory nerve end and synapses using an excitotoxic cochlear organotypic model and found that ROCK inhibitors could regenerate the cochlear nerve axons and synapses between the inner hair cell (IHC) and the auditory nerve after excitotoxic injury of the cochlea [17]. Based on these findings, we hypothesized that ROCK inhibitors would exert their effects on synaptic remodeling even in an in vivo model of cochlear synaptopathy
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