The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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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“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]
Citations
Cites
Oxygen free radicals and iron in relation to biology and medicine: Some problems and concepts
Halliwell, B., & Gutteridge, J. M. C. (1986) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(86)90305-x · Cited by 2,038
Role of metals in oxygen radical reactions
Aust, S. D., Morehouse, L. A., & Thomas, C. E. (1985) · Journal of Free Radicals in Biology & Medicine · doi:10.1016/0748-5514(85)90025-x · Cited by 1,150
Gutteridge, J. M. C. (1986) · FEBS Letters · doi:10.1016/0014-5793(86)80626-3 · Cited by 629
The involvement of iron in lipid peroxidation. Importance of ferric to ferrous ratios in initiation.
Braughler, J. M., Duncan, L. A., & Chase, R. L. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)67521-0 · Cited by 585
Gutteridge, J. M. C. (1984) · Biochemical Journal · doi:10.1042/bj2240761 · Cited by 306
Evidence suggesting a role for hydroxyl radical in gentamicin-induced acute renal failure in rats.
Walker, P. D., & Shah, S. V. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113325 · Cited by 298
Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex
Priuska, E. M., & Schacht, J. (1995) · Biochemical Pharmacology · doi:10.1016/0006-2952(95)02160-4 · Cited by 287
Self-citationThe protective effects of allopurinol and superoxide dismutase on noise‐induced cochlear damage
Seidman, M. D., Shivapuja, B. G., & Quirk, W. S. (1993) · Otolaryngology · doi:10.1177/019459989310900613 · Cited by 205
Gentamicin enhanced production of hydrogen peroxide by renal cortical mitochondria
Walker, P. D., & Shah, S. V. (1987) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1987.253.4.c495 · Cited by 148
Attenuation of gentamicin ototoxicity by glutathione in the guinea pig in vivo
Garetz, S. L., Altschuler, R. A., & Schacht, J. (1994) · Hearing Research · doi:10.1016/0378-5955(94)90255-0 · Cited by 142
Self-citation
Research works printed but not linked: 2
- Evenson, 1995, MTBA as a protective agent for cisplatin ototoxicity, Abstr. Assoc. Res. Otolaryngol., 18, 81
- Wang, 1996, The iron embrace: exposing the secret activities of gentamicin, Abst. Assoc. Res. Otolaryngol., 19, 29
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Forge, A., & Schacht, J. (2000) · Audiology and Neurotology · doi:10.1159/000013861 · Cited by 629
Self-citationAminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice
Barton-Davis, E. R., Cordier, L., Shoturma, D. I., Leland, S. E., & Sweeney, H. L. (1999) · Journal of Clinical Investigation · doi:10.1172/jci7866 · Cited by 579
Kell, D. B. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-2 · Cited by 554
Sha, S., Taylor, R., Forge, A., & Schacht, J. (2001) · Hearing Research · doi:10.1016/s0378-5955(01)00224-6 · Cited by 408
Self-citationMechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection
Huth, M. E., Ricci, A. J., & Cheng, A. G.-L. (2011) · International Journal of Otolaryngology · doi:10.1155/2011/937861 · Cited by 390
Metadata
- 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
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › 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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