This application request support for research directed at examining specific biochemical determinants which may mediate drug-induced ototoxicity during postnatal cochlear development. The proposed research will test the hypothesis that the ornithine decarboxylase (ODC)-polyamine system plays a crucial role in cochlear development and that inhibition of the ODS-polyamine system mediates the hypersensitivity of developing animals to ototoxic drug-induced teratogenecity. Normal cell growth and differentiation require polyamines, concentrations of which are highly regulated by the enzyme ODC. ODC activity, high at the onset of development, rapidly declines to adult levels by the end of functional development. Inhibition of ODC during this period results in functional deficits. To date, the ODC-polyamine system in the cochlear tissues of the developing rat has not been studied. Preliminary findings indicate age-related differences in cochlear ODC during postnatal days 10-25 which correspond to the documented period in this species of functional maturation and hypersensitivity to ototoxic drugs. ODC activity, highest on day 10, declined to adult levels by the 20th postnatal day. The goals of the proposed research include quantification of ODC and the polyamines putrescine, spermidine, and spermine during postnatal cochlear development followed by an examination of the effects of inhibitors of ODC including gentamicin and a-difluromethylornithine (DFMO) on the ODC- polyamine system and ont the functional maturation of the cochlea. Onset and maturation of cochlear function will be assessed by acoustic distortion products. ODC activity will be quantitated by measuring the amount of 14 CO2 liberated in the decarboxylation of 14 C-ornithine, while polyamine tissue levels will be quantified by high-pressure liquid chromatography utilizing flurometric detection. During functional maturation (postnatal days 10-25), the rat is hypersensitive to ototoxic drugs. Drug-induced inhibition of the ODC- polyamine system during cochlear development may be responsible of this increased susceptibility. Reports of ototoxicity with DFMO and aminoglycoside inhibition of ODC suggest that alterations in polyamine metabolism may mediate ototoxicity. Comparison of the effects of DFMO and gentamicin on the ODC-polyamine system with effects on the functional development of the inner ear promises to result in a greater understanding of the role of polyamines in cochlear development and the hypersensitivity period of ototoxicity.
| Muszynski, C A; Robertson, C S; Goodman, J C et al. (1993) DFMO reduces cortical infarct volume after middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 13:1033-7 |
