title: Role of glutathione in protection against noise-induced hearing loss.
abstract: A potential mechanism of hearing loss due to acoustic overstimulation is the generation of reactive oxygen species (ROS). ROS not removed by antioxidant defenses could be expected to cause significant damage to the sensory cells of the cochlea. We studied the influence of the antioxidant glutathione (GSH) on noise-induced hearing loss by using l-buthionine-[S,R]-sulfoximine (BSO), an inhibitor of GSH synthesis, and 2-oxothiazolidine-4-carboxylate (OTC), a cysteine prodrug, which promotes rapid restoration of GSH when GSH is acutely depleted. Pigmented female guinea pigs were exposed to broadband noise (102 dB SPL, 3 h/day, 5 days) while receiving daily injections of BSO, OTC, or saline. By weeks 2 and 3 after noise exposure, BSO-treated animals showed significantly greater threshold shifts above 12 kHz than saline-treated subjects, whereas OTC-treated animals showed significantly smaller threshold shifts at 12 kHz than controls. Histologically assessed noise-induced damage to the organ of Corti, predominantly basal turn row 1 outer hair cells, was most pronounced in BSO-treated animals. High performance liquid chromatographic analysis showed that OTC significantly increased cysteine levels, but not GSH levels, in the cochlea. These findings show that GSH inhibition increases the susceptibility of the cochlea to noise-induced damage and that replenishing GSH, presumably by enhancing availability of cysteine, attenuates noise-induced cochlear damage.
authors.affiliation: Kresge Hearing Research Institute, The University of Michigan, 1301 East Ann Street, Ann Arbor, MI 48109-0506, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yamasoba
authors.forename: A L
authors.initials: AL
authors.lastname: Nuttall
authors.forename: C
authors.initials: C
authors.lastname: Harris
authors.forename: Y
authors.initials: Y
authors.lastname: Raphael
authors.forename: J M
authors.initials: JM
authors.lastname: Miller
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001309:Auditory Threshold; D019328:Buthionine Sulfoximine / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology; D005260:Female; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D006168:Guinea Pigs; D006317:Hearing Loss, Noise-Induced / Q000473:pathology / Q000517:prevention & control*; D011355:Prodrugs / Q000627:therapeutic use*; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles / Q000627:therapeutic use*; D053778:Thiazolidines
chemical_list: D000975:Antioxidants; D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; D019328:Buthionine Sulfoximine; D005978:Glutathione; D003545:Cysteine; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid