Abstract
The Mongolian gerbil, Meriones unguiculatus, has been widely employed as a model for studies of the inner ear. In spite of its established use for auditory research, no robust protocols to induce ototoxic hair cell damage have been developed for this species. In this paper, we demonstrate the development of an aminoglycoside-induced model of hair cell loss, using kanamycin potentiated by the loop diuretic furosemide. Interestingly, we show that the gerbil is relatively insensitive to gentamicin compared to kanamycin, and that bumetanide is ineffective in potentiating the ototoxicity of the drug.We also examine the pathology of the spiral ganglion after chronic, long-term hair cell damage. Remarkably, there is little or no neuronal loss following the ototoxic insult, even at 8 months post-damage. This is similar to the situation often seen in the human, where functioning neurons can persist even decades after hair cell loss, contrasting with the rapid, secondary degeneration found in rats, mice and other small mammals. We propose that the combination of these factors makes the gerbil a good model for ototoxic damage by induced hair cell loss.
Highlights
Since their introduction in the 1940s, aminoglycoside antibiotics have been recognised clinically for their off-target effects of ototoxicity
The destruction of the three rows of outer hair cells and single row of inner hair cells would eventually lead to loss of the surrounding supporting cells and the replacement of the organ with a flattened epithelium of scar tissue, and accompanying profound deafness in Abbreviations: SGN, Spiral Ganglion Neuron; Auditory brainstem response (ABR), Auditory Brainstem Response; PFA, Paraformaldehyde; ethylenediaminetetraacetic acid (EDTA), Ethylenediaminetetraacetic acid; PBS, Phosphate Buffered Saline; BSA, Bovine Serum Albumin; DAPI, 4,6-diamidino-2phenylindole; MSBB, Methyl salicylate and Benzyl benzoate; ANOVA, Analysis of variance; round window membrane (RWM), Round window membrane; OHC, Outer hair cells; IHC, Inner hair cells; myelin basic protein (MBP), Myelin basic protein
As the field of regenerative medicine moves forward, this damaged epithelium becomes a potential target for therapeutic intervention, whether it be the idea of recreating the organ of Corti, or in its role as a model for cochlear implantation studies
Summary
Since their introduction in the 1940s, aminoglycoside antibiotics have been recognised clinically for their off-target effects of ototoxicity. When used in combination therapy with a loop diuretic such as ethacrynic acid, the often-reversible deafness seen with the antibiotic alone was rapidly induced and permanent (Brown et al, 1974; Mathog et al, 1969). Such damage was found to be caused by the death of the sensory cells of the specialised hearing epithelium, the organ of Corti, located within the bony shell of the cochlea. A sequela to the death of the organ of Corti is often the secondary loss of the spiral ganglion neurons (SGNs) which innervate the hair cells This loss occurs with varying rapidity in different species. For instance in the guinea pig, a substantial abrogation of SGNs is observed 7 days after aminoglycoside treatment (Kong et al, 2010), whereas in human patients, remaining SGNs have been found several decades after hair cell loss is thought to have occurred (Ghorayer et al, 1980)
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