Pre-treatment With Fasudil Prevents Neomycin-Induced Hair Cell Damage by Reducing the Accumulation of Reactive Oxygen Species

Abstract

Ototoxic drug-induced hair cell (HC) damage is one of the main causes of sensorineural hearing loss, which is one of the most common sensory disorders in humans. Aminoglycoside antibiotics are common ototoxic drugs, and these can cause the accumulation of intracellular oxygen free radicals and lead to apoptosis in HCs. Fasudil is a Rho kinase inhibitor and vasodilator that has been widely used in the clinic and has been shown to have neuroprotective effects. However, the possible application of fasudil in protecting against aminoglycoside-induced HC loss and hearing loss has not been investigated. In this study, we investigated the ability of fasudil to protect against neomycin-induced HC loss both in vitro and in vivo. We found that fasudil significantly reduced the HC loss in cochlear whole-organ explant cultures and reduced the cell death of auditory HEI-OC1 cells after neomycin exposure in vitro. Moreover, we found that fasudil significantly prevented the HC loss and hearing loss of mice in the in vivo neomycin damage model. Furthermore, we found that fasudil could significantly inhibit the Rho signaling pathway in the auditory HEI-OC1 cells after neomycin exposure, thus further reducing the neomycin-induced accumulation of reactive oxygen species and subsequent apoptosis in HEI-OC1 cells. This study suggests that fasudil might contribute to the increased viability of HCs after neomycin exposure by inhibition of the Rho signaling pathway and suggests a new therapeutic target for the prevention of aminoglycoside-induced HC loss and hearing loss.

Loss of Cochlear Ribbon Synapse Is a Critical Contributor to Chronic Salicylate Sodium Treatment-Induced Tinnitus without Change Hearing Threshold

“…HCs in the cochlea play a critical role in converting mechanical sound waves into neural signals for hearing [19][20][21]. Most hearing loss induced by noise, different ototoxic drugs, inflammation, or aging is caused by the HC damage [22][23][24][25][26][27][28][29]. Ribbon synapses are vital structures between inner HC and SGNs, which are the primary synaptic structures in the sound conduction pathway and play an important role in sound signal transmission [30][31][32].…”

Stem Cell-Based Therapeutic Approaches to Restore Sensorineural Hearing Loss in Mammals

“…Most of the hearing loss patients have the same pathological features in common such as the HC loss and the decreased number of SGNs [11,12]. Ototoxic insult to the sensory HCs causes hair cell death, which is mainly due to the exposure to loud noise, use of aminoglycosides or chemotherapy regimens, viral infections, biological aging, and genetically inherited disorders [13][14][15][16][17][18][19][20]. The drug-induced damage also promotes the reduction of specialized synaptic structures between IHCs and SGNs followed by the later degeneration of SGN [21][22][23].…”

Involvement of Cholesterol Metabolic Pathways in Recovery from Noise-Induced Hearing Loss

“…Hair cells in the cochlea play a critical role in converting mechanical sound waves into neural signals for hearing [3][4][5]. Previous studies using mouse models showed that acoustic injury of the auditory system is caused by multiple factors, and most of the hearing loss induced by noise, different ototoxic drugs, infection, or aging are caused by the hair cells damage [6][7][8][9][10][11][12][13]. Impulse noise (>140 dB SPL) causes hearing loss primarily through mechanical damage of hair cells [14], while steady noise causes metabolic damage of hair cells [15].…”