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Dynamic changes following combined treatment with gentamicin and ethacrynic acid with and without acoustic
1INSERM Research Unit 229, University of Bordeaux II, France.
Abstract:
Regional selectivity of gentamicin (GM) ototoxicity was studied in guinea pigs (GPs) using electrophysiological, morphological, autoradiographic and immunohistological observations following combined treatment with GM (150 mg/kg i.m.) and ethacrynic acid (EA) (30 mg/kg i.c. or i.v., 1.5 h after GM injection). The GPs were either continuously stimulated every 5 min with a series of 256 clicks (70 dB peSPL, 10/s) during 3 h for monitoring fast changes in VIII nerve compound action potential (CAP) after the EA injection, and thereafter kept in the animal quarters (background noise of 60 dB SPL) (group I), or similarly monitored for only 10 min after the EA injection and thereafter kept in a soundproof room (around 0 dB SPL) (group II). Whenever GM labelling was observed it was localized only in the sensory hair cells. From 3 h after EA injection, the GPs in group I presented threshold elevations in the high-frequency region, which progressed to 60-80 dB at all frequencies at and after 48 h. Parallel to the threshold pattern, GM uptake in outer hair cells (OHCs) was seen with an increasing concentration from apex toward base from 3 to 24 h, while after 48 h almost all OHCs were destroyed and inner hair cells (IHCs) were marked by GM. In group II no changes in CAP thresholds were observed until more than 24 h, although GM was detected in the hair cells from 6 h on. At this early stage, the distribution of GM lacked a clear pattern, particularly without a clear apex-base gradient, and GM deposits were found only around the basal body. However in both groups, in late stage (greater than 24 h), the base-apex gradient was more pronounced and GM was found throughout the cell body, with a marked concentration below the cuticular plate. These results suggest that GM may penetrate hair cells around the basal body and that activating the cells by sound potentiates both GM uptake and its intracellular toxicity.
Insights
Sound exposure potentiates gentamicin uptake and toxicity in guinea pig hair cells, particularly in the cochlear base. This study reveals how sound activation influences aminoglycoside ototoxicity.
Area of Science:
- Ototoxicity research
- Auditory neuroscience
- Pharmacology
Background:
- Gentamicin (GM) is an aminoglycoside antibiotic known to cause ototoxicity.
- Ethacrynic acid (EA) is a diuretic that can enhance GM ototoxicity.
- The regional selectivity and mechanisms of GM-induced hair cell damage remain under investigation.
Purpose of the Study:
- To investigate the regional selectivity of gentamicin ototoxicity in guinea pigs.
- To examine the influence of sound stimulation on GM uptake and toxicity in cochlear hair cells.
Main Methods:
- Guinea pigs were treated with gentamicin (GM) and ethacrynic acid (EA).
- Electrophysiological (CAP thresholds), morphological, autoradiographic, and immunohistological methods were employed.
- Two groups were studied: one with continuous sound stimulation and one with minimal sound exposure.
Main Results:
- Sound stimulation (Group I) led to rapid high-frequency threshold elevations and widespread outer hair cell (OHC) destruction within 48 hours.
- In contrast, minimal sound exposure (Group II) delayed threshold changes beyond 24 hours, despite early GM detection in hair cells.
- Gentamicin uptake showed an apex-to-base gradient, concentrating in OHCs initially, then inner hair cells (IHCs), particularly in the cochlear base, with sound exposure enhancing this pattern and intracellular toxicity.
Conclusions:
- Gentamicin appears to penetrate hair cells via the basal body.
- Sound activation significantly potentiates both gentamicin uptake and its intracellular toxicity.
- These findings highlight the role of acoustic activity in the regional selectivity of aminoglycoside-induced ototoxicity.