sirolimus and Hearing-Loss--Noise-Induced

Reactive oxygen species play a dual role in mediating both cell stress and defense pathways. Here, we used pharmacological manipulations and siRNA silencing to investigate the relationship between autophagy and oxidative stress under conditions of noise-induced temporary, permanent, and severe permanent auditory threshold shifts (temporary threshold shift [TTS], permanent threshold shift [PTS], and severe PTS [sPTS], respectively) in adult CBA/J mice.. Levels of oxidative stress markers (4-hydroxynonenal [4-HNE] and 3-nitrotyrosine [3-NT]) increased in outer hair cells (OHCs) in a noise-dose-dependent manner, whereas levels of the autophagy marker microtubule-associated protein light chain 3 B (LC3B) were sharply elevated after TTS but rose only slightly in response to PTS and were unaltered by sPTS noise. Furthermore, green fluorescent protein (GFP) intensity increased in GFP-LC3 mice after TTS-noise exposure. Treatment with rapamycin, an autophagy activator, significantly increased LC3B expression, while diminishing 4-HNE and 3-NT levels, reducing noise-induced hair cell loss, and, subsequently, noise-induced hearing loss (NIHL). In contrast, treatment with either the autophagy inhibitor 3-methyladenine (3MA) or LC3B siRNA reduced LC3B expression, increased 3-NT and 4-HNE levels, and exacerbated TTS to PTS.. This study demonstrates a relationship between oxidative stress and autophagy in OHCs and reveals that autophagy is an intrinsic cellular process that protects against NIHL by attenuating oxidative stress.. The results suggest that the lower levels of oxidative stress incurred by TTS-noise exposure induce autophagy, which promotes OHC survival. However, excessive oxidative stress under sPTS-noise conditions overwhelms the beneficial potential of autophagy in OHCs and leads to OHC death and NIHL.

Topics: Acetylcysteine; Aldehydes; Animals; Antioxidants; Autophagy; Hair Cells, Auditory, Outer; Hearing Loss, Noise-Induced; Male; Mice; Microtubule-Associated Proteins; Oxidative Stress; Sirolimus; Tyrosine

This study examined the effect of immunosuppressants, cyclosporin A, FK506 and rapamycin on functional recovery of the cochlea after acoustic overexposure, in guinea pigs and mice. Thirty guinea pigs were exposed to a 2 kHz pure tone at 120 dB SPL for 10 min. The compound action potential threshold shift induced by acoustic overexposure was examined. Twenty-five mice were exposed to a 4 kHz pure tone at 128 dB SPL for 4h. Auditory brainstem response was used to examine the hearing threshold shift. In both the guinea pig and mouse experiments, cyclosporin A and FK506, intraperitonally given just before acoustic overexposure, significantly decreased the hearing threshold shift one or two weeks after acoustic overexposure. However, neither rapamycin nor the FK506 and rapamycin combined treatment groups showed improvement of the threshold shift. The present findings suggest that these two calcineurin inhibitors have a protective effect against acoustic injury of the cochlea, whereas the non-calcineurin inhibitor, rapamycin, not only has no effect against acoustic injury, but rather blocked the effect of FK506. This indicated a possible role of calcineurin against acoustic injury.

Topics: Action Potentials; Analysis of Variance; Animals; Audiometry, Pure-Tone; Brain Stem; Calcineurin Inhibitors; Cochlea; Cyclosporine; Electrophysiology; Female; Guinea Pigs; Hair Cells, Auditory, Outer; Hearing Loss, Noise-Induced; Immunosuppressive Agents; Mice; Mice, Inbred Strains; Protective Agents; Sirolimus; Species Specificity; Tacrolimus