Autophagic flux, a possible mechanism for delayed gentamicin-induced ototoxicity

Area of Science:

• Ototoxicity research
• Cellular autophagy mechanisms
• Pharmacology of antibiotics

Background:

• Aminoglycoside antibiotics like gentamicin (GM) can cause delayed ototoxicity and hearing loss.
• The precise mechanisms underlying GM-induced delayed ototoxicity remain unclear.
• Autophagy plays a critical role in cellular homeostasis and stress response.

Purpose of the Study:

• To investigate the role of autophagy in the delayed ototoxic effects of gentamicin.
• To elucidate the cellular mechanisms of gentamicin-induced auditory cell death.
• To explore potential therapeutic strategies for mitigating GM ototoxicity.

Main Methods:

• In vitro studies using HEI-OC1 auditory cells treated with gentamicin.
• In vivo studies involving intraperitoneal injection of gentamicin in animal models.
• Analysis of autophagosome markers (LC3-II), lysosomal proteins (Rab7, cathepsin D), and cell viability.
• Assessment of hearing thresholds and LC3 accumulation in the organ of Corti.

Main Results:

• Gentamicin treatment increased LC3-II levels and cell death in auditory cells, indicating autophagosome accumulation.
• GM-treated autophagosomes showed reduced Rab7 levels, suggesting impaired autophagic flux.
• Rapamycin, an autophagy enhancer, upregulated Rab7 and cathepsin D, improving cell survival.
• In vivo, GM worsened hearing and increased LC3 in the cochlea, effects attenuated by rapamycin.

Conclusions:

• Delayed gentamicin ototoxicity is linked to impaired autophagy and autophagosome accumulation.
• Enhancing autophagic flux may be a viable strategy to inhibit GM-induced auditory cell death.
• This study provides insights into the molecular basis of aminoglycoside-induced hearing loss.