Kanamycin depletes cochlear polyamines in the developing rat.
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.
Henley
C M
CM
Department of Otorhinolaryngology/Communicative Sciences and Pharmacology, Baylor College of Medicine, Houston, TX 77030.
D000704:Analysis of Variance; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D003051:Cochlea / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D007612:Kanamycin / Q000633:toxicity*; D051381:Rats
D015317:Biogenic Polyamines; D007612:Kanamycin