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Kanamycin depletes cochlear polyamines in the developing rat
1Department of Otorhinolaryngology/Communicative Sciences and Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Insights
Developing mammals show heightened sensitivity to aminoglycoside ototoxicity during cochlear maturation. This study reveals impaired polyamine synthesis, suggesting a mechanism for this developmental hypersensitivity.
Area of Science:
- Ototoxicology
- Developmental Biology
- Neuroscience
Background:
- Developing mammals exhibit increased susceptibility to ototoxic agents like aminoglycoside antibiotics.
- Maximum sensitivity coincides with the cochlea's anatomic and functional maturation, particularly during the second and third postnatal weeks in rats.
- Aminoglycoside ototoxicity initially manifests as outer hair cell (OHC) damage in the basal cochlea, detectable via distortion-product otoacoustic emissions (DPOAEs).
Purpose of the Study:
- To investigate the underlying mechanism of developmental hypersensitivity to aminoglycoside-induced ototoxicity.
- To explore the role of the ornithine decarboxylase (ODC)-polyamine pathway in mediating this heightened sensitivity.
- To characterize the polyamine response to aminoglycoside exposure during the critical developmental period.
Main Methods:
- Assessing outer hair cell (OHC) function using distortion-product otoacoustic emissions (DPOAEs) in developing rats.
- Measuring ornithine decarboxylase (ODC) activity in the cochlea.
- Analyzing polyamine levels (spermidine, spermine, putrescine) in the organ of Corti following aminoglycoside administration.
Main Results:
- Aminoglycoside exposure during development led to an incomplete polyamine response in the organ of Corti.
- Specifically, spermidine and spermine levels were inhibited, while putrescine accumulated.
- These findings suggest aminoglycoside-induced inhibition of polyamine synthesis occurs during development.
Conclusions:
- Aminoglycoside ototoxicity in developing mammals may be mediated by the disruption of polyamine synthesis.
- Interference with polyamine pathways, crucial for developmental and repair processes, likely underlies the observed hypersensitivity.
- Targeting the ODC-polyamine pathway could offer strategies to mitigate developmental ototoxicity.
Abstract:
Developing mammals are more sensitive to aminoglycoside antibiotics and other ototoxic agents than adults, with maximum sensitivity occurring during the period of anatomic and functional maturation of the cochlea. For the aminoglycoside antibiotics, the hypersensitive period in rats occurs during the second and third postnatal weeks. Toxicity is initially expressed as outer hair cell (OHC) damage in the high-frequency, basal region of the cochlea. Distortion-product otoacoustic emissions (DPOAEs), physiologic measures of OHC function, are particularly sensitive to aminoglycoside exposure during the period of rapid cochlear physiologic development. Toxicity is characterized by increased DPOAE thresholds and decreased amplitudes. The mechanism of developmental sensitivity to aminoglycosides is unknown. A potential biochemical target of aminoglycosides is the ornithine decarboxylase (ODC)-polyamine pathway. ODC activity is elevated in the developing rat cochlea, aminoglycosides inhibit cochlear ODC in developing rats, and alpha-difluoromethylornithine (a specific ODC inhibitor) impairs development of cochlear function. In the present study we demonstrate an incomplete polyamine response to aminoglycoside damage, characterized by inhibition of the polyamines spermidine and spermine and accumulation of putrescine in the organ of Corti. Aminoglycoside inhibition of polyamine synthesis may mediate developmental ototoxic hypersensitivity by interfering with developmental and repair processes.