Protection from Gentamicin Ototoxicity by Iron Chelators in Guinea Pig In Vivo,
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 x 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.
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Gentamicin can form a gentamicin-iron complex that can lead to toxic symptoms such as hearing loss; this is reversed by iron chelators.
“Thus, gentamicin can form a gentamicin-iron complex that can lead to toxic symptoms such as hearing loss; this is reversed by iron chelators [1788,1789].”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [1788]
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- Authors
- Song, B.-B., Anderson, D. J., & Schacht, J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Schacht, Jochen
- ORCID
- Schacht, Jochen
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1997-07
- Volume
- 282
- Issue
- 1
- Pages
- 369-377
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1916770705
- Cited by
- 111
- References
- 37
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 1 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 2
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institute on Deafness and Other Communication Disorders (DC-00124)
- Topics
- Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Chemotherapy-induced organ toxicity mitigation
- Life Sciences › Neuroscience › Neurology › Vestibular and auditory disorders
- Keywords
- gentamicin ototoxicity, aminoglycoside ototoxicity, iron chelators, 2,3-dihydroxybenzoate, deferoxamine, free radicals, hearing threshold shift, vestibular toxicity, radical scavengers, mannitol, guinea pig, drug-induced hearing loss
- MeSH terms
- Animals, Anti-Bacterial Agents, Gentamicins, Guinea Pigs, Hearing Disorders, Iron, Iron Chelating Agents, Male, Serum Albumin, Weight Gain, Evoked Potentials, Auditory, Brain Stem, Nystagmus, Optokinetic
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