Postexposure treatment with a Src-PTK inhibitor in combination with N-l-acetyl cysteine to reduce noise-induced hearing loss

Abstract

Both the antioxidant, N-l-acetyl cysteine (NAC), and the Src inhibitor, KX1-004, have been used to protect the cochlea from hazardous noise. In order to extend our previous work on KX1-004 with noise exposure, the current studies were undertaken with two goals: (1) to test the effectiveness of NAC and KX1-004 in combination with one another when given in a protection paradigm, and (2) to test the NAC+KX1-004 combination in a postexposure rescue paradigm. The noise exposure for the first experiment consisted of a 4-kHz octave band of noise at 107 dB SPL for 2 hours. The combination of NAC and KX1-004 were administered either prior to the noise exposure or post exposure (rescue). The second experiment was undertaken to extend the findings of the first experiment's rescue paradigm. The 4 kHz octave band noise was delivered at 112 dB SPL for 1 hour, with the experimental drugs delivered only in a rescue paradigm. In Experiment 1, animals treated before the 2-hour noise exposure with the combination of NAC and KX1-004 had from 12 to 17 dB less permanent threshold shift when compared to control saline treated animals. Treatment in the rescue paradigm did not produce any reductions in threshold shift from the 2-hour exposure. In the second experiment, with the 1-hour noise, rescue with KX1-004 or KX1-004 plus NAC yielded small, but significant, reductions in threshold shift. There was no additional benefit from the combination of NAC and KX1-004 over KX1-004 by itself.