Fursultiamine Prevents Drug-Induced Ototoxicity by Reducing Accumulation of Reactive Oxygen Species in Mouse Cochlea.

Ye-Ri Kim,In-Kyu Lee,Kyu-Yup Lee,Jeong-In Baek,Tae-Jun Kwon,Un-Kyung Kim

doi:10.3390/antiox10101526

Abstract

Drug-induced hearing loss is a major type of acquired sensorineural hearing loss. Cisplatin and aminoglycoside antibiotics have been known to cause ototoxicity, and excessive accumulation of intracellular reactive oxygen species (ROS) are suggested as the common major pathology of cisplatin- and aminoglycoside antibiotics-induced ototoxicity. Fursultiamine, also called thiamine tetrahydrofurfuryl disulfide, is a thiamine disulfide derivative that may have antioxidant effects. To evaluate whether fursultiamine can prevent cisplatin- and kanamycin-induced ototoxicity, we investigated their preventive potential using mouse cochlear explant culture system. Immunofluorescence staining of mouse cochlear hair cells showed that fursultiamine pretreatment reduced cisplatin- and kanamycin-induced damage to both inner and outer hair cells. Fursultiamine attenuated mitochondrial ROS accumulation as evidenced by MitoSOX Red staining and restored mitochondrial membrane potential in a JC-1 assay. In addition, fursultiamine pretreatment reduced active caspase-3 and TUNEL signals after cisplatin or kanamycin treatment, indicating that fursultiamine decreased apoptotic hair cell death. This study is the first to show a protective effect of fursultiamine against cisplatin- and aminoglycoside antibiotics-induced ototoxicity. Our results suggest that fursultiamine could act as an antioxidant and anti-apoptotic agent against mitochondrial oxidative stress.in cochlear hair cells.

Highlights

We examined the protective effects of FT treatment on cochlear hair cell viability, apoptotic signaling, reactive oxygen species (ROS) levels, and mitochondria membrane potential in mouse cochlear explants treated with cisplatin alone (CP) or aminoglycoside kanamycin (KM)
In the untreated CT group, inner hair cells (IHCs) and outer hair cells (OHCs) showed intact arrangement from the apex to the base. Both 30 μM CP and 1.2 mM KM disturbed the arrangement of both IHCs and OHCs (Figure 1A), with a more pronounced breakdown of stereocilia bundles in OHCs than in
The organ of Corti, stria vascularis, and spiralthe ganglia are the main appears to occur in these regions simultaneously, the hair cells in the organ of Corti have affected by drug‐induced ototoxicity

Summary

Introduction

Acquired hearing loss is known as one of the most common sensory disorders. 6% of the world’s population currently has hearing loss, with more than 2 billion people predicted to have hearing loss by 2050 [1]. The major causes of acquired hearing loss include infection, trauma, noise, injury, and ototoxic drugs. Two major classes of ototoxic drugs induce permanent hearing loss: aminoglycoside antibiotics and platinum-based chemotherapeutic agents. Both types of drugs damage inner ear hair cells through accumulation of ROS that triggers a pro-inflammatory response cascade including caspase 3 activation [2], limiting their clinical application

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Conclusion