Time course of cochlear electrophysiology and morphology after combined administration of kanamycin and furosemide

Abstract

In animal models of deafness, administration of an aminoglycoside in combination with a loop diuretic is often applied to produce a rapid loss of cochlear hair cells. However, the extent to which surviving hair cells remain functional after such a deafening procedure varies. In a longitudinal electrocochleographical study, we investigated the variability of cochlear function between and within guinea pigs after combined administration of kanamycin and furosemide. Concurrently, histological data were obtained at 1, 2, 4 and 8 weeks after deafening treatment. The main measures in our study were compound action potential (CAP) thresholds, percentage of surviving hair cells and packing density of spiral ganglion cells (SGCs). One day after deafening treatment, we found threshold shifts widely varying among animals from 0 to 100 dB. The variability decreased after 2 days, and in 18 out of 20 animals threshold shifts greater than 55 dB were found 4-7 days after deafening. Remarkably, in the majority of animals, thresholds decreased by up to 25 dB after 7 days indicating functional recovery. As expected, final thresholds were negatively correlated to the percentage of surviving hair cells. Notably, the percentage of surviving hair cells might be predicted on the basis of thresholds observed one day after deafening. SGC packing density, which rapidly decreased with the period after deafening treatment and correlated to the percentage of surviving inner hair cells, was not a determining factor for the CAP thresholds.

Auditory-Nerve Responses to Varied Inter-Phase Gap and Phase Duration of the Electric Pulse Stimulus as Predictors for Neuronal Degeneration

“…Ototoxic treatment involved subcutaneous injection of kanamycin (Sigma-Aldrich, St. Louis, MO, USA; 400 mg/kg) and subsequent infusion of furosemide (Centrafarm, Etten-Leur, The Netherlands; 100 mg/kg) into the external jugular vein, which has been shown to eliminate the great majority of both inner and outer hair cells (Versnel et al 2007;West et al 1973). Postoperatively, the animals were injected subcutaneously with the nonototoxic antibiotic enrofloxacin (Baytril®, 5 mg/kg) and the anti-inflammatory drug carprofen (Rimadyl®, 5 mg/kg).…”

“…Proper functioning of CIs thus depends on the presence of a healthy and sufficiently large population of SGCs that is able to transduce the encoded auditory information to the brainstem. However, animal studies have shown that SGCs become smaller and degenerate as a consequence of hair cell loss (Ylikoski et al 1974;Spoendlin 1975;Webster and Webster 1981;Versnel et al 2007). This degeneration has been associated with discontinued neurotrophic support from the organ of Corti (Ernfors et al 1995;Fritzsch et al 1999;Zilberstein et al 2012).…”

Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

“…30 After the preliminary AABR measurement, 400 mg/kg kanamycine were injected subcutaneously. In the next two hours, the jugular vein was exposed under incision of the overlaying musculature in order to inject the loop diuretic furosemide (100 mg/kg).…”

Combined Administration of Kanamycin and Furosemide Does Not Result in Loss of Vestibular Function in Guinea Pigs

“…However, single high-dose application of an aminoglycoside given concurrently with a loop diuretic (e.g. ethacrynic acid, furosemide) results in massive loss of cochlear hair cells, already within days [West et al, 1973;Russell at al., 1979;Brummett, 1981;Webster and Webster, 1981;Xu et al, 1993;McFadden et al, 2004;Nourski et al, 2004;Versnel et al, 2007]. Since the first clinical observations of this potentiating effect [Mathog and Klein, 1969;Johnson and Hamilton, 1970;Meriwether et al, 1971], treatment protocols based upon concomitant administration of an aminoglycoside and a loop diuretic have been used extensively to induce rapid hair cell loss in experimental animal models of deafness.…”