Ethacrynic acid regulates gentamicin ototoxicity via the blood-labyrinth barrier

Area of Science:

• Ototoxicity research
• Pharmacology
• Neuroscience

Background:

• Gentamicin (GM), an aminoglycoside antibiotic, causes ototoxicity, limiting its clinical use.
• Co-administration with other drugs can exacerbate GM-induced ototoxicity.
• Understanding these interactions is crucial for patient safety.

Purpose of the Study:

• To investigate the ototoxic mechanisms of gentamicin combined with ethacrynic acid (EA).
• To evaluate the protective effects of N-acetylcysteine (NAC) against combined GM and EA toxicity.
• To explore the role of the blood-labyrinth barrier (BLB) in GM ototoxicity.

Main Methods:

• Systematic investigation using C57BL/6 J mice.
• Dose-dependent administration of GM and EA.
• Evaluation of cochlear hair cell loss, auditory nerve degeneration, and spiral ganglion neuron damage.
• Assessment of systemic hepatorenal toxicity markers.
• Analysis of BLB integrity and pericyte-mediated repair.
• Intervention with N-acetylcysteine (NAC) at different time points.

Main Results:

• GM induced dose-dependent ototoxicity, with intravenous administration being more severe.
• EA synergistically potentiated GM ototoxicity, causing significant hair cell loss and neural degeneration.
• EA disrupted BLB integrity and triggered compensatory repair mechanisms.
• NAC intervention significantly attenuated combined GM and EA toxicity, with pretreatment showing the best results.
• Delayed EA administration reduced hair cell damage, and NAC ameliorated neural and synaptic damage.

Conclusions:

• Ethacrynic acid exacerbates gentamicin ototoxicity by disrupting blood-labyrinth barrier homeostasis.
• N-acetylcysteine provides significant protection against combined gentamicin and ethacrynic acid ototoxicity.
• The timing of N-acetylcysteine administration is critical for its protective efficacy, offering a potential strategy for preventing drug-induced hearing loss.