Calcineurin activation contributes to noise-induced hearing loss.

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.