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

Background and Objectives: The antioxidant ebselen will be able to limit or prevent the ototoxicity arising from 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). Niemann-Pick Type C (NPC) disease is a disorder of lysosomal storage manifested in sphingolipidosis. Recently, it was noted that experimental use of HP beta CD could partially resolve the symptoms in both animals and human patients. Despite its desirable effect, HP beta CD can induce hearing loss, which is the only major side effect noted to date. Understanding of the pathophysiology of hearing impairment after administration of HP beta CD and further development of preventive methods are essential to reduce the ototoxic side effect. The mechanisms of HP beta CD-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 HP beta CD-induced ototoxicity, we tested the efficacy of an antioxidant reagent, ebselen, on the extent of inner ear side effects caused by HP beta CD. Materials and Methods: Ebselen was applied prior to administration of HP beta CD in mice. Auditory brainstem response thresholds and otopathology were assessed one week later. Bilateral effects of the drug treatments also were examined. Results: HP beta CD-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 HP beta CD-induced hearing loss or after the resulting histopathology. Conclusions: The results indirectly suggest that cochlear damage by HP beta CD is unrelated to reactive oxygen species formation. However, further research into the mechanism(s) of HP beta CD otopathobgy is necessary.