Chinchilla models of selective cochlear hair cell loss

• Published in: Hearing research Vol. 174; no. 1; pp. 230 - 238
• Main Authors: McFadden, Sandra L, Ding, Dalian, Jiang, Haiyan, Woo, Jenifer M, Salvi, Richard J
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.12.2002; Elsevier
• Subjects: Aminoglycoside antibiotic; Animals; Anti-Bacterial Agents - administration & dosage; Biological and medical sciences; Body Weight - drug effects; Cell Death; Chinchilla; Cochlea - drug effects; Cochlea - pathology; Cochlea - physiology; Diuretics - administration & dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Drug toxicity and drugs side effects treatment; Ethacrynic Acid - administration & dosage; Free radical; Gentamicins - administration & dosage; Hair Cells, Auditory - drug effects; Hair Cells, Auditory - pathology; Hair Cells, Auditory - physiology; Hair Cells, Vestibular - drug effects; Hair Cells, Vestibular - physiology; Hearing loss; Inner ear pathology; Loop diuretic; Medical sciences; Ototoxicity; Pharmacology. Drug treatments; Toxicity: respiratory system, ent, stomatology; Loop diuretic; Aminoglycoside antibiotic; OHC, outer hair cell; GM, gentamicin sulfate; IHC, inner hair cell; AAB, aminoglycoside antibiotics; EA, ethacrynic acid; Inner ear pathology; ROS, reactive oxygen species; Free radical; Ototoxicity; Hearing loss; Cell function; Toxicity; Gentamicin; Auditory disorder; Etacrynic acid; Chinchilla; Organ of hearing; Diuretic; ENT disease; Vestibular system; Hair cell of the ear; Internal ear disease; Rodentia; Vertebrata; Antibiotic; Mammalia; Cell death; Aminoglycoside; Cochlea
• ISSN: 0378-5955; 1878-5891
• DOI: 10.1016/S0378-5955(02)00697-4

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 ∼100% loss of outer hair cells and dose-dependent losses of inner hair cells, ranging from ∼100% to 58%. In 1 and 1.5 h delay groups, inner hair cell losses were ∼19% and 0%, outer hair cell losses were ∼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.