Abstract
This study details the prevention of gentamicin-induced hearing loss in guinea pig in vivo. The approach is based on our recent demonstrations of a redox-active gentamicin-iron complex in vitro and partial attenuation of gentamicin-induced hearing loss by the iron chelators deferoxamine and 2,3-dihydroxybenzoate. In our study, guinea pigs receiving injections of gentamicin (120 mg/kg body weight daily × 19 days) developed a progressive threshold shift reaching 50 to 70 dB at 18 kHz. Concurrent treatment with different doses of 2,3-dihydroxybenzoate (30–300 mg/kg/day) reduced the threshold shift to 25 to 15 dB. Coinjection of gentamicin with dihydroxybenzoate (100 mg/kg/day) plus mannitol (15 mg/kg/day) yielded complete functional and morphological protection from gentamicin ototoxicity although partial protection was observed with combinations of dihydroxybenzoate and deferoxamine. Dihydroxybenzoate also attenuated gentamicin-induced vestibular toxicity. The iron chelators and radical scavengers affected neither serum levels nor the antimicrobial efficacy of gentamicin against Escherichia coli. These results confirm that iron and free radicals play a crucial role in the toxic side effects of gentamicin. Furthermore, they suggest that iron chelators, which are well-established drugs in clinical therapy, may be promising therapeutic agents to reduce aminoglycoside ototoxicity.
Footnotes
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Send reprint requests to: Dr. Jochen Schacht, Kresge Hearing Research Institute, 1301 East Ann Street, Ann Arbor, MI 48109-0506.
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↵1 This work was supported by research Grant DC-00124 from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health.
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↵2 A preliminary report was presented at the 19th Midwinter Meeting of the Association for Research in Otolaryngology, St. Petersburg Beach, FL, February, 1996.
- Abbreviations:
- ABR
- auditory brainstem responses
- DHB
- 2,3-dihydroxybenzoic acid
- DFO
- deferoxamine mesylate
- GM
- gentamicin
- GSH
- glutathione
- MANN
- mannitol
- OHC
- outer hair cell
- PBS
- phosphate-buffered saline
- Received September 30, 1996.
- Accepted March 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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