tacrolimus and Hearing-Loss--Noise-Induced

The calcineurin inhibitor tacrolimus (TCR) and the pineal gland hormone and antioxidant melatonin (MLT) have been shown to possess otoprotective properties against noise-induced hearing loss (NIHL). In contrast, dexamethasone (DXM) was not effective as an otoprotective agent against NIHL. Further studies are needed to understand the exact molecular mechanisms involved.. Exposure to noise pollution and use of audio devices for long periods of time at high volume is known to cause hearing loss or NIHL. Our goal was to evaluate the effectiveness of various known compounds such as the anti-inflammatory DXM, the antioxidant MLT and the immunosuppressant TCR against NIHL.. Thirty-two Wistar rats were randomly divided into groups that were then exposed to intense white noise at 120 dB SPL for 4 h. The day before and for a period of 14 days, test groups were administered one of the three compounds. The efficacy of the compounds against NIHL was determined after examining the shifts in the levels of distortion product otoacoustic emissions (DPOAEs) and changes in the threshold of auditory brainstem responses (ABRs). Cytocochleograms and determination of gene expression in whole rat cochlea were carried out at day 21.. Treatment with DXM had no otoprotective effect, while animals treated with MLT experienced an improvement in their hearing functionality. This effect, which is probably linked to MLT's ability to reduce c-fos and TNF-alpha gene expression thereby preventing outer hair cell (OHC) loss, was even more pronounced in week 3. For its part, TCR provided protection against injury to the cochlea from week 1, eventually leading to a full recovery in hearing. The compound reduced both c-fos and TNF-alpha expression, as well as OHC loss.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Dexamethasone; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory, Outer; Hearing Loss, Noise-Induced; Immunosuppressive Agents; Male; Melatonin; Otoacoustic Emissions, Spontaneous; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Tacrolimus; Tumor Necrosis Factor-alpha

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

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.

Topics: Acoustic Stimulation; Animals; Calcineurin; Calcineurin Inhibitors; Cell Death; Cochlea; Cyclosporine; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Enzyme Inhibitors; Evoked Potentials, Auditory, Brain Stem; Functional Laterality; Guinea Pigs; Hair Cells, Auditory; Hearing Loss, Noise-Induced; Immunohistochemistry; Male; Peptides, Cyclic; Sensory Thresholds; Tacrolimus; Time Factors