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.
Institut de Recherches Biomédicales des Armées, 24 avenue des maquis du Grésivaudan, BP 87, 38702 La Tronche, France.
Loubna
L
Abaamrane
Florent
F
Raffin
Sébastien
S
Schmerber
Isabelle
I
Sendowski
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D005389:Firearms; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D007263:Infusions, Parenteral; D007976:Leupeptins / Q000627:therapeutic use*; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C032854:leupeptin
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