title: Calcineurin activation contributes to noise-induced hearing loss.
abstract: Acoustic overstimulation increases Ca(2+) concentration in auditory hair cells. Because calcineurin is known to activate cell death pathways and is controlled by Ca(2+) and calmodulin, this study assessed the role of calcineurin in auditory hair cell death in guinea pigs after intense noise exposure. Immediately after noise exposure (4-kHz octave band, 120 dB, for 5 hr), a population of hair cells exhibited calcineurin immunoreactivity at the cuticular plate, with a decreasing number of positive-stained cells on Days 1-3. By Day 7, the levels of calcineurin immunoreactivity had diminished to near control, non-noise exposed values, concomitant with an increasing loss of hair cells. Staining of hair cell nuclei with propidium iodide (PI), restricted to calcineurin-immunopositive cells, indicated breakdown of cell membranes symptomatic of incipient cell death. The local application of the calcineurin inhibitors, FK506 and cyclosporin A, reduced the level of noise-induced auditory brain stem response threshold shift and hair cell death, indicating that calcineurin is a factor in noise-induced hearing loss. The results suggest that calcineurin inhibitors are of potential therapeutic value for long-term protection of the morphologic integrity and function of the organ of Corti against noise trauma.
authors.affiliation: Kresge Hearing Research Institute, University of Michigan, 1301 E. Ann Street, Ann Arbor, MI 48109-0506, USA. josef@umich.edu
authors.forename: Shujiro B
authors.initials: SB
authors.lastname: Minami
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamashita
authors.forename: Jochen
authors.initials: J
authors.lastname: Schacht
authors.forename: Josef M
authors.initials: JM
authors.lastname: Miller
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D019703:Calcineurin / Q000378:metabolism / Q000502:physiology*; D065095:Calcineurin Inhibitors; D016923:Cell Death / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D007839:Functional Laterality; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism*; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism* / Q000517:prevention & control; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D010456:Peptides, Cyclic / Q000378:metabolism; D012684:Sensory Thresholds / Q000187:drug effects / Q000528:radiation effects; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; C017613:phallacidin; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus