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Calcineurin activation contributes to noise‐induced hearing loss

Acoustic overstimulation increases Ca2+ concentration in auditory hair cells. Because calcineurin is known to activate cell death pathways and is controlled by Ca2+ 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. © 2004 Wiley‐Liss, Inc.