The development of a therapeutic strategy to prevent aminoglycoside- induced hearing loss seems more urgent than ever. Millions of patients are treated annually in the US; worldwide, aminoglycosides are the most commonly used antibiotics. The problem is aggravated by the global resurgence of tuberculosis and the increased occurrence of resistant bacteria which necessitate multi-drug regimens including aminoglycosides. Given the 10 to 20 percent incidence of cochlear and vestibular disturbances associated with aminoglycoside treatment, this constitutes a major health problem in the US and abroad. The goal of the proposed research is to develop a rational protective treatment against aminoglycoside-ototoxicity. The anticipated studies are founded on exciting recent discoveries from this laboratory that allow the proposal of a mechanism of toxicity and a pharmacological means of protection. The first successful tests of the proposal of a mechanism of toxicity and a pharmacological means of protection. The first successful tests of the protective strategy have already been completed in guinea pig. The approach is based on the novel hypothesis that gentamicin can chelate iron. The iron-gentamicin complex catalyzes free-radical reactions which are toxic to the cell. These reactions can be inhibited by radical scavengers and, most dramatically, by iron chelators which attenuate gentamicin-induced hearing loss in guinea pigs in vivo. The goals of the proposal will be primarily accomplished by experiments on prevention or amelioration of aminoglycoside otoxicity in guinea pigs in vivo. In vitro and in vivo experiments will establish efficacious and safe combinations of iron chelators and scavengers. These goals are aided by structural and chemical analyses of the iron-aminoglycoside complexes which will improve our understanding of the underlying mechanisms and guide the development of protective strategies. These questions will be addressed with well-established biochemical, physiological, analytical and physicochemical techniques. The prevention or amelioration of adverse effects of aminoglycoside antibiotics will have far reaching implications for the continued but safe use of a family of drugs whose primary efficacy is unquestioned.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003685-03
Application #
6176172
Study Section
Hearing Research Study Section (HAR)
Program Officer
Freeman, Nancy
Project Start
1998-05-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
3
Fiscal Year
2000
Total Cost
$276,176
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Yang, Chao-Hui; Schrepfer, Thomas; Schacht, Jochen (2015) Age-related hearing impairment and the triad of acquired hearing loss. Front Cell Neurosci 9:276
Oishi, N; Duscha, S; Boukari, H et al. (2015) XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death. Cell Death Dis 6:e1763
Duscha, Stefan; Boukari, Heithem; Shcherbakov, Dimitri et al. (2014) Identification and evaluation of improved 4'-O-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics. MBio 5:e01827-14
Oishi, Naoki; Kendall, Ann; Schacht, Jochen (2014) Metformin protects against gentamicin-induced hair cell death in vitro but not ototoxicity in vivo. Neurosci Lett 583:65-9
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Oishi, Naoki; Chen, Jun; Zheng, Hong-Wei et al. (2013) Tumor necrosis factor-alpha-mutant mice exhibit high frequency hearing loss. J Assoc Res Otolaryngol 14:801-11
Chen, Fu-Quan; Zheng, Hong-Wei; Schacht, Jochen et al. (2013) Mitochondrial peroxiredoxin 3 regulates sensory cell survival in the cochlea. PLoS One 8:e61999
Chen, Fu-Quan; Hill, Kayla; Guan, Ya-Jun et al. (2012) Activation of apoptotic pathways in the absence of cell death in an inner-ear immortomouse cell line. Hear Res 284:33-41
Oishi, Naoki; Talaska, Andra E; Schacht, Jochen (2012) Ototoxicity in dogs and cats. Vet Clin North Am Small Anim Pract 42:1259-71

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