Cochlear pathology induced by aminoglycoside ototoxicity during postnatal maturation in cats

Abstract

Cochlear pathology resulting from neonatal administration of the aminoglycoside antibiotic, neomycin sulfate, was studied in young kittens at 15–24 days postnatal. Hearing thresholds showed severe to profound hearing loss in all but one animal. Scanning electron microscopy demonstrated that initial hair cell degeneration occurred in the extreme base (hook region) of the cochlea and sequentially progressed to the basal, middle, then the apical coil of the cochlea. The first row of outer hair cells degenerated first, followed by row 2, then row 3; the last cells to degenerate in a given region were the inner hair cells. This pattern of hair cell degeneration is similar to that seen in adults with neomycin ototoxicity. In contrast, the spiral ganglion exhibited a different pattern of degeneration with initial cell loss occurring in the middle of the cochlea, about 40–60% from the base (≈2.8–8 kHz). Thus, neuronal degeneration apparently is not secondary to sensory cell loss, but rather comprises an independent process in these neonatal animals. Taken together, the findings suggest that the spiral ganglion cell loss in the middle cochlear turn results from increased aminoglycoside sensitivity associated with an earlier initial onset of function in these neurons as compared to other cochlear regions.

Introduction

An animal model of congenital or very early acquired profound deafness has been developed in order to investigate the effects of chronic electrical stimulation delivered by a cochlear implant in the deafened, developing auditory system, (Leake et al., 1991, Leake et al., 1992, Leake et al., 1995; Snyder et al., 1990, Snyder et al., 1991, Snyder et al., 1995). Newborn kittens received daily injections of the aminoglycoside antibiotic, neomycin sulfate, administered beginning the first day after birth and continuing for 15–22 days. Previously published results showed that in these neonatally deafened cats, there is a striking difference between the pattern of ganglion cell degeneration and the pattern of damage to the organ of Corti when evaluated at intervals of about 4 months to more than a year after deafening (Leake et al., 1991, Leake et al., 1992). Specifically, the pattern of ganglion cell degeneration showed maximum loss in the middle segments of the cochlea, in the region approximately 40–60% from the cochlear base. In contrast, the organ of Corti in these same ears showed a very different pattern of induced degeneration. Since there were no surviving hair cells in these profoundly deafened cats, the condition of the organ of Corti was assessed by evaluating the degeneration of supporting cells using a rank-order grading method. Data showed that the maximum damage occurred in the basal extreme of the cochlea, with progressively better preservation of organ of Corti cytoarchitecture at more apical locations. It should be noted that this latter basal-to-apical progression is the typical pattern of damage that is observed both in the organ of Corti and in the spiral ganglion in animals deafened as adults by neomycin (Leake and Hradek, 1988). In fact, the degeneration of the spiral ganglion neurons following ototoxic drug administration has been considered in many previous studies to be secondary to hair cell degeneration – specifically, secondary to the loss of inner hair cells and the consequent collapse and degeneration of the pillar cells (Kohenen, 1965; Ylikoski, 1974; Johnsson, 1974; Bohne, 1976; Kiang et al., 1976; Hawkins et al., 1977; Johnsson et al., 1981; Nadol, 1981). Thus, it is very interesting that the pattern of spiral ganglion degeneration is apparently different from the pattern of organ of Corti degeneration in cats that are neonatally deafened.

To further elucidate the mechanisms underlying these phenomena, a scanning electron microscopic (SEM) study of the organ of Corti was conducted in order to investigate the initial pattern and sequence of hair cell degeneration in these neonatally deafened animals. A range of survival times was chosen to bracket the time when the auditory system would be expected to achieve adult-like sensitivity in normal cats, which is about P20 (Walsh and Romand, 1992), and to ensure a wide range in the extent of hair cell degeneration within the experimental group. Our working hypothesis was that the initial hair cell degeneration would occur in the extreme base with hair cell loss progressing over time toward the apex, as has been described in adults and as predicted by the pattern of supporting cell degeneration observed in older neonatally deafened cats. This result would suggest that ganglion cell degeneration is not simply secondary to sensory cell degeneration in the neonatally deafened animal, but rather comprises an independent process. Alternatively, the pattern of hair cell degeneration in the neonates could be different from adults and could correlate with and explain the unusual pattern of spiral ganglion cell loss observed in the neonatally deafened animals.