Conservation of endocochlear potential in mice with profound hearing loss induced by co-administration of kanamycin and furosemide

Abstract

Research in mammalian hair cell regeneration is hampered by a lack of in vivo model of adult mouse inner ear injury. In the present study we investigated the effects of a combination of a single dose of aminoglycoside followed by a loop diuretic in adult mice. The auditory brainstem response threshold shift, extent and defining characteristics of the cochlear lesion were assessed and verified at different time points post-treatment. Our data indicated that this drug combination caused the rapid and extensive death of outer hair cells (OHCs). OHC death presented throughout the cochlea that commenced in the basal turn by 24 h and progressed apically. In contrast, inner hair cell (IHC) loss was delayed and mild. Terminal deoxynucleotidyl transferase dUTP nick end labelling-positive nuclei demonstrated that the majority of OHCs died via an apoptotic pathway. Auditory threshold shifts of up to 90 dB SPL indicated a profound hearing loss. In addition, the endocochlear potential (EP) in the drug-treated animals displayed a significant decline at 12 h post-treatment followed by recovery by 48 h post-treatment. Despite this recovery, there was a significant and progressive decrease in strial vascularis thickness, which was predominantly due to atrophy of marginal cells. The present study reproduced an adult mouse model of aminoglycoside-induced hearing loss. The mechanism underlying the recovered EP in the model with extensive hair cell death is discussed.

Expression of EFR3A in the Mouse Cochlea during Degeneration of Spiral Ganglion following Hair Cell Loss

“…Kanamycin (Sigma, USA) at a concentration of 75 mg/ml and furosemide (Tianjin Pharmaceutical Group, Tianjin, China) at a concentration of 10 mg/ml were freshly prepared before use. All experimental animals were administered first with a subcutaneous injection of kanamycin (1 mg/g) and then with an intraperitoneal injection of furosemide (0.4 mg/g) 30–45 minutes after [ 14 ]. The experimental animals were grouped as 1 day, 5 days, 15 days, 30 days and 60 days after injection.…”

A validation study of auditory function in an aminoglycoside-furosemide ototoxicity mouse model: Auditory brainstem response and distortion product otoacoustic emissions

“…Furosemide and other loop diuretics have well-known synergistic effects with aminoglycoside antibiotics when the two drugs are administered together and cause profound hearing loss. 17,18 Upon combined treatment with each drug, i.e. after administration of an aminoglycoside antibiotic followed by a loop diuretic, complete OHC loss with IHC damage has been observed in our previous study.…”

Striatin Is Required for Hearing and Affects Inner Hair Cells and Ribbon Synapses

“…Furthermore, a recent study shows that disruption of cochlear gap junction-mediated intercellular communication (GJIC) in the spiral ligament specifically induces OHC cell death (Nishiyama et al, 2019). The damaging effects of aminoglycoside antibiotics on the cochlea are also much more extensive on OHCs as compared to their effects on IHCs (Xiong et al, 2011). Interestingly, in mice lacking the Kcc4 co-transporter that is expressed in hair and supporting cells, at P21, OHCs were almost totally lost, whereas IHCs were still present (Boettger et al, 2002).…”

“…The stria vascularis produces the endolymph extracellular fluid (Patuzzi, 2011) and generates an EP that is essential for normal auditory function (Quraishi and Raphael, 2008;Xiong et al, 2011). The TJs in the organ of Corti are required to form the cation-junctional barrier between perilymph and endolymph and to maintain the EP (Florian et al, 2003;Kitajiri et al, 2004).…”