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, o...
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Published in | Hearing research Vol. 174; no. 1; pp. 230 - 238 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
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Elsevier B.V
01.12.2002
Elsevier |
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Abstract | 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. |
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AbstractList | 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. 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. |
Author | Jiang, Haiyan Ding, Dalian Salvi, Richard J McFadden, Sandra L Woo, Jenifer M |
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Keywords | 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 |
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Snippet | Although it is well known that ethacrynic acid (EA) can enhance gentamicin (GM) ototoxicity, there has been no systematic study of the relationship between... |
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SubjectTerms | 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 |
Title | Chinchilla models of selective cochlear hair cell loss |
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