Chinchilla models of selective cochlear hair cell loss.
Although it is well known that ethacrynic acid (EA) can enhance gentamicin (GM) ototoxicity, there has been no systematic study of the relationship between dosing parameters and inner ear pathology. We examined the effects of two parameters, GM dose and time delay between GM and EA administration, on cochlear and vestibular hair cell loss in chinchillas. 'No delay' groups received one injection of GM (125, 40, 20, or 10 mg/kg i.m.) followed immediately by EA (40 mg/kg i.v.); 'delay' groups received GM (10 mg/kg i.m.) followed by EA 1 or 1.5 h later. Animals were sacrificed 7 days later for evaluation of hair cell loss in the cochlea and vestibular end organs (cristae, saccule and utricle). Vestibular function was assessed prior to sacrifice by measuring the duration of nystagmus induced by cold caloric stimulation. No delay groups had approximately 100% loss of outer hair cells and dose-dependent losses of inner hair cells, ranging from approximately 100% to 58%. In 1 and 1.5 h delay groups, inner hair cell losses were approximately 19% and 0%, outer hair cell losses were approximately 74% and 47%, and outer hair cell loss followed a typical base to apex gradient. Two results were remarkable. First, the three groups with partial inner hair cell loss showed an atypical lesion pattern in which losses were substantially greater in the apical half than in the basal half of the cochlea. Second, there was no vestibular pathology in any group. The results establish dosing parameters that can be used to produce animal models with defined patterns and magnitudes of cochlear hair cell damage, but normal vestibular function and morphology.
McFadden
Sandra L
SL
Center for Hearing and Deafness, 215 Parker Hall, University at Buffalo, Buffalo, NY 14214, USA. mcfadden@buffalo.edu
Ding
Dalian
D
Jiang
Haiyan
H
Woo
Jenifer M
JM
Salvi
Richard J
RJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death; D002682:Chinchilla; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D004232:Diuretics / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004976:Ethacrynic Acid / Q000008:administration & dosage*; D005839:Gentamicins / Q000008:administration & dosage*; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D018069:Hair Cells, Vestibular / Q000187:drug effects / Q000502:physiology
D000900:Anti-Bacterial Agents; D004232:Diuretics; D005839:Gentamicins; D004976:Ethacrynic Acid