The aim of these interdisciplinary studies is the elucidation of biochemical mechanisms underlying aminoglycoside-induced hearing loss. Specifically, we wish to describe the molecular events leading to inner ear damage; to establish structure-toxicity relationships and develop in-vitro tests for ototoxicity; and to define conditions of reversibility or amelioration of toxic effects. The work is based on previously obtained results and begins with the hypothesis that these antibiotics bind to polyphosphoinositide lipids, displace calcium, and disturb membrane structure and function. The studies will combine biochemical, physicochemical, electrophysiological, and morphological techniques. The interaction of aminoglycosides with phosphatidylinositol bisphosphate is quantitated by physicochemical measurements, e.g., with monomolecular lipid films, differential scanning calorimetry or permeability changes of liposomes. Structurally modified drugs are tested as to their lipid binding and their effect on cochlear microphonics and action potentials in perilymphatic perfusions in order to determine those sites on the antibiotic that are involved in its ototoxic action. Drug/lipid interactions in monolayers will also be investigated for their usefulness as an in-vitro correlate of drug ototoxicity. Pharmacokinetic studies will determine the distribution of preferentially cochleotoxic and vestibulotoxic aminoglycosides in the inner ear and this will be compared to phosphoinositide content in these structures. Reversibility of gentamicin-induced hearing loss, previously established in cochlear perfusions, will be explored after systemic injection of the drug. The proposed studies should expand our understanding of the biochemical mechanisms underlying aminoglycoside ototoxicity and provide guidance for drug modification and amelioration of toxic effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS013792-09
Application #
3395318
Study Section
Hearing Research Study Section (HAR)
Project Start
1977-09-01
Project End
1991-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cammer, W; Zhang, H (1993) Lectin binding by macroglial and microglial cells in the brains of young normal and myelin-deficient (md) mutant rats. Glycobiology 3:627-31
Huang, M; Dulon, D; Schacht, J (1990) Outer hair cells as potential targets of inflammatory mediators. Ann Otol Rhinol Laryngol Suppl 148:35-8
Forge, A; Zajic, G; Davies, S et al. (1989) Gentamicin alters membrane structure as shown by freeze-fracture of liposomes. Hear Res 37:129-39
Huang, M Y; Schacht, J (1989) Drug-induced ototoxicity. Pathogenesis and prevention. Med Toxicol Adverse Drug Exp 4:452-67
Dulon, D; Zajic, G; Aran, J M et al. (1989) Aminoglycoside antibiotics impair calcium entry but not viability and motility in isolated cochlear outer hair cells. J Neurosci Res 24:338-46
Dulon, D; Zajic, G; Schacht, J (1989) Photo-induced irreversible shortening and swelling of isolated cochlear outer hair cells. Int J Radiat Biol 55:1007-14
Riaz, M; Weiner, N D; Schacht, J (1989) Separation of liposome populations differing in phosphoinositide content by chromatography on immobilized neomycin. J Pharm Sci 78:172-5
Henley 3rd, C M; Mahran, L G; Schacht, J (1988) Inhibition of renal ornithine decarboxylase by aminoglycoside antibiotics in vitro. Biochem Pharmacol 37:1679-82
Henley 3rd, C M; Schacht, J (1988) Pharmacokinetics of aminoglycoside antibiotics in blood, inner-ear fluids and tissues and their relationship to ototoxicity. Audiology 27:137-46
Williams, S E; Zenner, H P; Schacht, J (1987) Three molecular steps of aminoglycoside ototoxicity demonstrated in outer hair cells. Hear Res 30:11-8

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