title: Selective loss of inner hair cells and type-I ganglion neurons in carboplatin-treated chinchillas. Mechanisms of damage and protection.
abstract: Carboplatin preferentially destroys inner hair cells (IHCs) and type-I spiral ganglion neurons while sparing outer hair cells (OHCs). Loss of IHCs and type-I ganglion cells is associated with a significant reduction of the compound action potential (CAP). However, the cochlear microphonic (CM) potential and distortion product otoacoustic emissions (DPOAEs) remain normal, indicating that the OHCs are functionally intact. In the vestibular system, carboplatin selectively destroys type-I hair cells and their afferent neurons. Damage of type-I vestibular hair cells and their afferent terminals is associated with significant depression of nystagmus induced by cold, caloric stimulation. Histochemical studies revealed a rapid decrease in succinate dehydrogenase (SDH) staining in IHCs soon after carboplatin treatment, and staining intensity remained depressed in surviving IHCs for at least 1 month after carboplatin treatment. These results suggest that carboplatin depresses the metabolic function in surviving IHCs. Several lines of evidence suggest that free radicals may contribute to carboplatin-induced sensory cell damage. Intracochlear infusion of L-buthionine-[S,R]-sulfoximine (BSO), which depletes intracellular glutathione (GSH), increases IHC and OHC loss. Previous in vitro studies have shown that neurotrophin 4/5 (NT-4/5) promotes the survival of spiral ganglion neurons from cisplatin ototoxicity. In vivo perfusion of NT-4/5 promoted the survival of spiral ganglion neurons, but did not protect the hair cells.
authors.affiliation: Hearing Research Lab, University of Buffalo, New York 14214, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Ding
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Salvi
authors.forename: D
authors.initials: D
authors.lastname: Henderson
authors.forename: B H
authors.initials: BH
authors.lastname: Hu
authors.forename: S L
authors.initials: SL
authors.lastname: McFadden
authors.forename: M
authors.initials: M
authors.lastname: Mueller
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016190:Carboplatin / Q000009:adverse effects*; D002682:Chinchilla; D003051:Cochlea / Q000187:drug effects / Q000502:physiology; D003638:Deafness / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects* / Q000502:physiology; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000502:physiology; D018069:Hair Cells, Vestibular / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D009414:Nerve Growth Factors; D017382:Reactive Oxygen Species; D016190:Carboplatin