Abstract
Aminoglycoside-induced hair cell (HC) loss is one of the most important causes of hearing loss. After entering the inner ear, aminoglycosides induce the production of high levels of reactive oxygen species (ROS) that subsequently activate apoptosis in HCs. Citicoline, a nucleoside derivative, plays a therapeutic role in central nervous system injury and in neurodegenerative disease models, including addictive disorders, stroke, head trauma, and cognitive impairment in the elderly, and has been widely used in the clinic as an FDA approved drug. However, its effect on auditory HCs remains unknown. Here, we used HC-like HEI-OC-1 cells and whole organ explant cultured mouse cochleae to explore the effect of citicoline on aminoglycoside-induced HC damage. Consistent with previous reports, both ROS levels and apoptosis were significantly increased in neomycin-induced cochlear HCs and HEI-OC-1 cells compared to undamaged controls. Interestingly, we found that co-treatment with citicoline significantly protected against neomycin-induced HC loss in both HEI-OC-1 cells and whole organ explant cultured cochleae. Furthermore, we demonstrated that citicoline could significantly reduce neomycin-induced mitochondrial dysfunction and inhibit neomycin-induced ROS accumulation and subsequent apoptosis. Thus, we conclude that citicoline can protect against neomycin-induced HC loss by inhibiting ROS aggregation and thus preventing apoptosis in HCs, and this suggests that citicoline might serve as a potential therapeutic drug in the clinic to protect HCs.
Highlights
MATERIALS AND METHODSSensorineural hearing loss remains a serious sensory disorder worldwide
We found that the viability of HEI-OC-1 cells decreased gradually with increasing neomycin doses and time, and 50–60% of the HEI-OC-1 cells were alive after being treated with 10 mM neomycin for 24 h
Cochlear hair cell (HC) are susceptible to aminoglycoside-mediated cytotoxicity and cannot be regenerated once damaged, and aminoglycoside ototoxicity is usually associated with permanent sensorineural deafness (Nadol, 1993; Lazarou et al, 2015; Correia-Melo et al, 2017)
Summary
Sensorineural hearing loss remains a serious sensory disorder worldwide. Once the hair cells (HCs) of the inner ear are damaged, sensorineural hearing loss is permanent due to the inability of mammalian HCs to regenerate. We used the HC-like House Ear Institute Organ of Corti 1 (HEI-OC-1) cell line along with explant cultured cochlear HCs to establish an in vitro neomycin-induced damage model in auditory HCs with the aim to investigate the potential protective effect of citicoline in auditory HCs. All animal procedures were performed according to protocols approved by the Animal Care and Use Committee of Southeast University, and all efforts were made to minimize the number of animals used and to prevent their suffering. After treating the HEI-OC-1 cells with citicoline and/or drugs, the cells were trypsinized and collected and washed twice with PBS and resuspended in binding buffer at a concentration of 1 × 106 cells/ml. After treating the HEI-OC-1 cells with citicoline and/or neomycin, the cells were trypsinized, collected, and resuspended in prewarmed solution containing Mito-SOX Red or TMRE for 10 min. A p-value < 0.05 was considered to be statistically significant
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