Elsevier

Brain Research

Volume 1134, 23 February 2007, Pages 122-130
Brain Research

Research Report
Electrophysiological correlates of progressive sensorineural pathology in carboplatin-treated chinchillas

https://doi.org/10.1016/j.brainres.2006.11.078Get rights and content

Abstract

Carboplatin produces progressive damage to auditory nerve fibers, spiral ganglion neurons (SGNs) and inner hair cells (IHC) in the chinchilla cochlea but leaves outer hair cells intact. Within 1 h after injection, many afferent terminals beneath IHCs and myelin lamellae surrounding SGN processes are vacuolated. One day after injection, approximately half of the nerve fibers are missing. IHCs are intact at 2 days, but 20–30% are missing at 3 days. We studied the electrophysiological correlates of this progressive morphological damage by recording cochlear microphonics (CM), distortion product otoacoustic emissions (DPOAE), summating potentials (SP), compound action potentials (CAP) and midbrain evoked potentials (IC-EVP) before and 1 h, 12 h, 1 days, 3 days, 5 days, 7 days and 14 days after carboplatin injection (75 mg/kg IP) in four chinchillas. CM and DPOAEs tended to be unchanged or enhanced. CAP and SP showed little change until Day 3, when amplitudes were reduced in all animals and CAP thresholds were elevated by 9 dB; amplitudes declined further between Days 3 and 5 but not thereafter. IC-EVP amplitudes decreased on Days 3 or 5 but thresholds were relatively unchanged. All animals showed some recovery of IC-EVP between Days 7 and 14, including one with 70% enhancement on Day 14. The results indicate that threshold and amplitude measures fail to detect peripheral pathology until some relatively high threshold level of damage has been exceeded. This has important implications for monitoring peripheral damage and interpreting electrophysiological test results in animals and humans.

Introduction

Carboplatin, a widely used platinum-based chemotherapy agent, produces an unusual and well documented pattern of damage in the peripheral auditory system of the chinchilla that is unlike the damage produced in other species, including rats, guinea pigs and humans. When administered at relatively low doses, carboplatin destroys sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) while leaving the outer hair cells (OHCs) intact and functioning (Ding et al., 1999, Ding et al., 2001, Hofstetter et al., 1997a, Hofstetter et al., 1997b, Trautwein et al., 1996, Takeno et al., 1994, Wake et al., 1993, Wake et al., 1996, Wang et al., 1997, Wang et al., 2003). Damage to the chinchilla cochlea and auditory nerve is rapid and progressive, with vacuolization of nerve terminals beneath IHCs and separation of myelin lamellae surrounding nerve fibers being the earliest observable effects (Ding et al., 1999, Ding et al., 2001, Wang et al., 2003). Wang et al. (2003) observed many small vacuoles in afferent terminals beneath IHCs and separation of myelin layers surrounding nerve fibers in the internal auditory meatus at 1 h after low-dose carboplatin injection (50 mg/kg IP). At 6 h post-injection, IHCs still appeared normal while afferent terminals were frequently swollen and myelin was more severely and extensively disrupted. Counts of nerve fibers in the habenula perforata showed losses of approximately 45% at 24 h, 55% at 48 h and 75% at 72 h post-injection, consistent with losses of approximately 50%, 60% and 80% at 24 h, 48 h and 72 h, respectively, following injection of a moderate dose (100 mg/kg) in a previous study (Ding et al., 2001). At 72 h, nearly all afferent terminals were severely swollen, ruptured or undergoing autolysis. In contrast to the rapid loss of nerve fibers (approximately half within 1 day following injection), IHC counts remained normal until 3 days post-injection, when approximately 20–30% of IHCs were missing.

In most previous studies of carboplatin-treated chinchillas, electrophysiological measurements were made weeks or months after injection, after SGN and IHC loss had stabilized. The aim of the present study was to investigate the effects of early morphological damage in the chinchilla cochlea and auditory nerve on peripheral and central auditory system functioning. Cochlear microphonics (CM) and distortion product otoacoustic emissions (DPOAE) were used to assess OHC function; summating potentials (SP) were used to monitor IHC function; compound action potentials (CAP) were measured to assess the functional integrity of the IHC/afferent fiber synapses and auditory nerve; and evoked potentials measured from the inferior colliculus (IC-EVP) were used to assess central auditory system functioning. By measuring changes in auditory physiology at various levels of the auditory system over time in carboplatin-treated chinchillas, we hoped to identify functional consequences attributable to myelin damage and nerve fiber loss (i.e., the early effects of carboplatin) and compare them to changes following SGN and IHC loss in the same animals.

Section snippets

Results

Hair cell loss 14 days after carboplatin injection is shown in Fig. 1. The pattern of damage was similar across the four animals, with IHC loss generally increasing from the apical end of the basilar membrane to the basal region. Losses peaked at 77–96% in the region of the basilar membrane representing frequencies between approximately 3 kHz to 9 kHz. OHC loss was negligible (< 2% across the cochlea) in all animals. Averaged across the four animals, IHC loss was 20.5% ± 6.0% in the apical half of

Discussion

We investigated the peripheral and central auditory effects of progressive damage to myelin, nerve fibers and IHCs in the chinchilla cochlea by recording CM, DPOAE, SP, CAP and IC-EVP at multiple times after carboplatin injection. In addition to showing the early physiological effects of carboplatin in this animal model, the results provide a novel perspective on the sensitivity and specificity of the various physiological measures themselves.

Subjects and electrode implantation surgery

Four adult chinchillas (Chinchilla laniger) obtained from a vendor licensed by the U.S. Department of Agriculture (Jarr Chinchilla Inc., Hubbard, OH) underwent surgery for implantation of three recording electrodes. Animals were anesthetized with an intramuscular injection of ketamine (50 mg/kg) and acepromazine (0.3 mg/kg) and placed on a Deltaphase® Isothermal Pad (Braintree Scientific, Inc., Braintree, MA) in a stereotaxic apparatus. A postauricular incision was made to expose the cochlear

Acknowledgments

This work was supported by NIDCD grant P01 DC03600 (SLM). The authors gratefully acknowledge Dalian Ding, Center for Hearing and Deafness, University at Buffalo, for preparing the cochleograms.

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