Abstract 418, Date 1:00 pm, Tuesday, February 22, 2005 (24 hours) Session O4: Inner Ear Ototoxic Injury: Mechanisms
Ethacrynic Acid Exacerbates Cisplatin-Induced Hair Cell Loss in Chinchillas and Reduces DPOAEs
*Andrew Baschnagel, Dalian Ding, Haiyan Jiang, Richard J. Salvi
Chinchillas show a dramatic difference in ototoxicity from two closely related platinum-based anticancer drugs, carboplatin versus cisplatin (CIS). High doses of carboplatin reliably induce massive inner hair cell (IHC) damage and substantially less outer hair cell (OHC) loss in chinchillas. In contrast, cisplatin typically leads to death of the chinchilla, but little hair cell loss. Since cisplatin-induced hair cell damage is extremely difficult to induce in chinchillas, we co-administered with CIS (0.2, 0.4 or 0.8 mg/kg, i.p.) and ethacrynic acid (EA, 40 mg/kg, i.v.) and determined the amount and pattern of CIS+EA induced hair cell destruction and the change in DPOAE amplitude. CIS alone resulted in little or no hair cell loss at these concentrations. However, when if EA was administered at the same time as CIS, there was rapid and widespread destruction of IHC and OHC and large reduction in DPOAE. The 0.8 mg/kg dose of CIS plus EA resulted in nearly total loss of IHC and OHC over the basal 80% of the cochlea and abolished DPOAEs at f2 frequencies 1200-12000 Hz. EA plus a CIS dose of 0.4 mg/kg resulted in a relatively flat IHC loss ranging from 50-80% throughout the cochlea; the OHC lesion showed the typical base-to-apex gradient with roughly 95% OHC loss in the basal half of the cochlea decreasing to 40% in the apex. EA plus 0.2 mg/kg of CIS resulted in a flat IHC lesion ranging from 30-60% throughout the cochlea and a gradient of OHC loss that decreased from 95% in the base to 10% in the apex. With the 0.2 mg/kg dose of CIS, DPOAEs were absent at the high frequencies and greatly reduced at the lowest frequencies where there was partial retention of OHC. Thus, CIS can induce massive hair cell lesions in chinchillas, but only when it is co-administered with EA. Combined treatment with CIS and EA results in a peculiar, flat IHC lesion reminiscent of that seen with carboplatin and the typical OHC loss gradient that decreases from base to apex. (Supported by NIH grants P01 DC03600-01A1 & R01 DC06630-01)