Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway.

Abstract

Aminoglycoside ototoxicity is a common cause of drug-induced hearing loss. Toxicity is dose related, but some patients may still develop hearing loss even under safe dosage. Apart for genetic idiosyncrasy, indirect evidences imply that ischemia may increase the aminoglycoside ototoxic sensitivity because common clinical situations associated with cochlear ischemia such as noise, sepsis, and shock are known to augment the development of aminoglycoside ototoxicity. At present, a direct interaction of cochlear ischemia and aminoglycoside ototoxicity is still lacking. This study demonstrated a direct evidence of increased gentamicin (GM) ototoxic sensitivity in chronic guinea pig models of transient cochlear ischemia. No permanent auditory changes were observed after a single dose of GM (125 mg/kg) or after transient cochlear ischemia for 30 min. Persistent and significant auditory threshold shift was detected when GM was given after transient cochlear ischemia. Cochlear hair cells and spiral ganglion neurons are the major regions affected. Apoptosis contributes to hair cell death during acute interaction of ischemia and GM ototoxicity. Increased apoptotic cell death was also depicted when GM crossreacted with hypoxia in vitro, using cochlear cell lines. Generation of reactive oxygen species, loss of mitochondrial membrane potential, calcium release, and caspase-dependent apoptotic cell death were shown during the interaction of hypoxia and GM ototoxicity in vitro. This synergistic ototoxicity may be critical to aminoglycoside-induced hearing loss in clinical scenarios. The results should improve our understanding of the interacting mechanism and potential preventive strategy to aminoglycoside ototoxicity.

• Authors: Chia-Der Lin, Ming-Ching Kao, Ming-Hsui Tsai, Chih-Ho Lai, I-Hua Wei, Mang-Hung Tsai, Chih-Hsin Tang, Cheng-Wen Lin, Chuan-Jen Hsu, Ching-Yuang Lin
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 91 Issue 7 Pg. 1092-106 (Jul 2011) ISSN: 1530-0307 [Electronic] United States
• PMID: 21519324 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Gentamicins
• Caspases

Topics

• Animals
• Anti-Bacterial Agents (adverse effects)
• Apoptosis
• Blotting, Western
• Caspases (metabolism)
• Cell Line
• Cochlea (blood supply, drug effects, metabolism)
• Disease Models, Animal
• Flow Cytometry
• Gentamicins (adverse effects)
• Guinea Pigs
• Hearing Loss (chemically induced)
• Hypoxia (physiopathology)
• Ischemia (physiopathology)