Intracochlear perfusion of leupeptin and z-VAD-FMK: influence of antiapoptotic agents on gunshot-induced hearing loss

The therapeutic efficiency of cochlear infusion of two anti-apoptotic substances: a potent calpain inhibitor, leupeptin and a caspase inhibitor, z-VAD-FMK was evaluated in guinea pigs after a gunshot noise-induced trauma (170 dB SPL). A preliminary study showed that hair cell apoptosis appeared within 7 days of the noise trauma. For each animal, one of the cochleae was perfused directly starting 1 h after the trauma with leupeptin or z-VAD-FMK for 7 days via a mini-osmotic pump whereas the other cochlea was untreated. ABR threshold shifts were measured over a 14-day recovery period. The functional hearing study was supplemented by histological analysis. Two days after the trauma significant differences were observed between threshold shifts in the z-VAD-FMK-treated and the non-treated ears. Cochleograms showed that hair cell losses were significantly lower in z-VAD-FMK-treated ears. Regarding the leupeptin treatment, no significant difference between treated and non-treated ears was observed. This work indicates that early direct infusion of z-VAD-FMK into the cochlea accelerates hearing recovery and reduces hair cell loss after gunshot noise-induced trauma. These results suggest that the gunshot noise-induced trauma may involve the caspase pathway rather than the calpain pathway in the apoptotic process.