J Audiol Otol.  2019 Apr;23(2):69-75. 10.7874/jao.2018.00255.

ROS Scavenger, Ebselen, Has No Preventive Effect in New Hearing Loss Model Using a Cholesterol-Chelating Agent

• Lee MY
• Kabara LL
• Swiderski
• Raphael Y
• Duncan RK
• Kim YH

• KMID: 2447576
• DOI: http://doi.org/10.7874/jao.2018.00255

Abstract

BACKGROUND AND OBJECTIVES
The antioxidant ebselen will be able to limit or prevent the ototoxicity arising from 2-hydroxypropyl-β-cyclodextrin (HPβCD). Niemann-Pick Type C (NPC) disease is a disorder of lysosomal storage manifested in sphingolipidosis. Recently, it was noted that experimental use of HPβCD could partially resolve the symptoms in both animals and human patients. Despite its desirable effect, HPβCD can induce hearing loss, which is the only major side effect noted to date. Understanding of the pathophysiology of hearing impairment after administration of HPβCD and further development of preventive methods are essential to reduce the ototoxic side effect. The mechanisms of HPβCD-induced ototoxicity remain unknown, but the resulting pathology bears some resemblance to other ototoxic agents, which involves oxidative stress pathways. To indirectly determine the involvement of oxidative stress in HPβCD-induced ototoxicity, we tested the efficacy of an antioxidant reagent, ebselen, on the extent of inner ear side effects caused by HPβCD.
MATERIALS AND METHODS
Ebselen was applied prior to administration of HPβCD in mice. Auditory brainstem response thresholds and otopathology were assessed one week later. Bilateral effects of the drug treatments also were examined.
RESULTS
HPβCD-alone resulted in bilateral, severe, and selective loss of outer hair cells from base to apex with an abrupt transition between lesions and intact areas. Ebselen co-treatment did not ameliorate HPβCD-induced hearing loss or alter the resulting histopathology.
CONCLUSIONS
The results indirectly suggest that cochlear damage by HPβCD is unrelated to reactive oxygen species formation. However, further research into the mechanism(s) of HPβCD otopathology is necessary.

Keyword

Cyclodextrin; Ebselen; Prestin; Tight junctions; Outer hair cell

MeSH Terms

Animals
Ear, Inner
Evoked Potentials, Auditory, Brain Stem
Hair Cells, Auditory, Outer
Hearing Loss*
Hearing*
Humans
Mice
Oxidative Stress
Pathology
Reactive Oxygen Species
Sphingolipidoses
Tight Junctions
Reactive Oxygen Species