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.
Highlights
Hearing loss is the most common sensory deficiency worldwide, and the number of people suffering from hearing loss is rising due to aging populations, ototoxic drug abuse, noise exposure, and environmental pollution
Because there are no reports of using fasudil to protect against ototoxic drug-induced hair cell (HC) loss, we first investigated the appropriate dose and treatment time of fasudil in the auditory cell line HEI-OC-1 before neomycin exposure
We found that the numbers of HCs in the apical turn of the cochlea showed no significant differences after neomycin exposure with or without fasudil treatment compared to the undamaged control group (Figures 2A,D, p > 0.05, n = 3)
Summary
Hearing loss is the most common sensory deficiency worldwide, and the number of people suffering from hearing loss is rising due to aging populations, ototoxic drug abuse, noise exposure, and environmental pollution. Ototoxic drugs (including many chemotherapeutics, loop diuretics, and aminoglycosides) induce hair cell (HC) damage and are the one of the common cause of sensorineural hearing loss (Tabuchi et al, 2011). Aminoglycoside antibiotics are widely used due to their low cost and effectiveness against serious infections caused by gram-negative bacteria, but these drugs can cause HC death by activating apoptosis and necrosis-related pathways (Sugahara et al, 2006; Tabuchi et al, 2011). When the drug enters the lymphatic space of the inner ear, the high-frequency region of the cochlea is the first to be damaged (Kroese et al, 1989)
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