Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo
Abstract
Recent studies from our laboratory have suggested that the ototoxic side effects of gentamicin are caused by a metabolized or 'activated' from the drug. Furthermore, we have postulated that the activation proceeds via the formation of an iron-gentamicin complex and that this complex produces free radicals. The present study assessed the protection effects of free radical scavengers and iron chelators on gentamicin-induced ototoxicity in guinea pigs in vivo. Gentamicin (120 mg/kg per day for 19 days) caused progressive threshold shifts reaching 50-65 dB at 18 kHz. Co-therapy with different radical scavengers yielded results ranging from no protection (with allopurinol, dimethyl sulfoxide, benzoate, lazaroid U74389G) to a moderate attenuation of hearing loss (with mannitol, 4-methylthiobenzoate, WR-2721). This finding agrees well with previous reports of inconsistent effects of scavengers on aminoglycoside-induced ototoxicity although it should be cautioned that only a single dose and route of application was tested. Two iron chelators, deferoxamine and 2,3-dihydroxybenzoate, significantly reduced the gentamicin-induced threshold shifts to about 10 dB or less. Iron chelators markedly decreased total serum iron levels while gentamicin treatment alone had no influence. There were no differences in serum gentamicin levels among all treated groups. This study confirms that iron plays a critical role in gentamicin ototoxicity and suggests 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 [1789]
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Gene Therapy and Stem Cell Transplantation: Strategies for Hearing Restoration
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- Authors
- Song, B.-B., & Schacht, J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Schacht, Jochen
- ORCID
- Schacht, Jochen
- Venue
- Hearing Research
- Publisher
- Elsevier BV
- Published
- 1996-05
- Volume
- 94
- Issue
- 1-2
- Pages
- 87-93
- ISSN
- 0378-5955 (ISSN-L)
- OpenAlex
- W2047770131
- Cited by
- 157
- References
- 41
- Citations by year
- 2026: 1 · 2024: 6 · 2023: 1 · 2020: 5 · 2019: 3 · 2018: 1 · 2017: 4 · 2016: 5 · 2015: 3 · 2014: 5 · 2013: 2 · 2012: 6
- FWCI
- 7.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hearing Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- 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, radical scavengers, iron chelators, threshold shift, deferoxamine, 2,3-dihydroxybenzoate, serum iron, guinea pig
- MeSH terms
- Administration, Oral, Allopurinol, Analysis of Variance, Animals, Anti-Bacterial Agents, Antimetabolites, Antioxidants, Auditory Threshold, Benzoates, Deferoxamine, Dimethyl Sulfoxide, Amifostine, Gentamicins, Guinea Pigs, Injections, Intraperitoneal, Injections, Subcutaneous, Iron, Iron Chelating Agents, Male, Mannitol, Pregnatrienes, Free Radical Scavengers, Hydroxybenzoates
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