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Noise-induced and age-related functional and structural cochlear alterations in Igf1-/+ mice

AutorCelaya, Adelaida M. ; Contreras, Julio ; Rodriguez-de la Rosa, Lourdes ; Zubeldia, José M. ; Varela-Nieto, Isabel
Fecha de publicación2014
CitaciónARO 2014
Resumen[Background]: The physiological age-related decrease in circulating IGF-I levels have been related to cognitive and brain alterations. Therefore, IGF-I is considered a neuroprotective agent. Human IGF-I deficiency is a rare disease associated with poor growth rates, mental retardation and syndromic hearing loss (OMIM608747). Igf1-/- mice are dwarfs with poor survival rates and congenital profound deafness, which worsens with ageing. Our objective was to compare the susceptibility of Igf1+/- and Igf1+/+ mice to damage by using exposure to excessive noise at different ages. [Methods]: Animals. Igf1+/- and Igf1+/+ mice were maintained in MF1OlaHsd*129/Sv genetic bakground. Hearing. Auditory Brainstem Responses (ABR) was performed with a Tucker Davis Technologies workstation before (pre) and 3, 14 and 28 days after noise exposure. Noise exposure. Mice were exposed awake in a sound reverberant chamber to a violet swept sine noise enriched in high frequencies as reported5 at 105 dB SPL for 30 minutes. Cochlear morphology and inmunohistochemistry. Cresyl-violet or hematoxilin-eosin staining of 10 mm cochlear paraffin and frozen sections. Serial frozen sections (10 mm) were collected to detect neurofilament and synaptophysin. Hair-cell quantification. Decalcified cochleae were mid-sectioned exposing ~80% of the whole extent of the basilar membrane. The organ of Corti (OC) was dissected and phalloidin-stained, and its total length was divided into equidistant 5% sectors as reported6 using stereological software (CAST®). The number of inner (IHC) and outer (OHC) hair cells in systematically randomly sampled areas were determined, and cell density (cells/1000 mm2) was estimated for each sector. RT-qPCR. RNA expression levels of cochlear genes involved in synaptogenesis, inflammation and cell cycle were analyzed by real time quantitative PCR using probes from TaqMan®. Serum determinations. IGF-I levels were determined using a specific ELISA assay (OCTEIA Rat/Mouse IGF-I kit, IDS Ltd.). Statistical analysis. A mixed model procedure with ANOVA or Student t-test was carried out with SPSS v19.0 software or with RealTime StatMiner® software for RT-qPCR data. Post hoc multiple comparisons included Bonferroni and Tamhane tests. Data are expressed as mean±SEM. The results were considered significant at p<0.05. [Results]: Igf1+/+ and Igf1+/- mice show an age-dependent decrease in IGF-I serum levels, especially from 6 months of age on, which correlates with the increase in ABR thresholds. Noise-exposure experiments with 1 and 3 months-old mice did not reveal differences between genotypes, both genotypes were equally sensible to NIHL. However, 6 month-old Igf1+/- presented greater susceptibility to noise damage, with higher threshold shifts and a poorer recovery compared to noise-exposed Igf1+/+ mice. The cellular and molecular mechanisms underlying susceptibility to damage will be discussed. [Conclusion]: These data suggest that IGF-I moderate deficit enhances otic sensibility to damage. Therefore, IGF-I-based therapies could contribute to prevent or ameliorate age-related and noise-induced hearing loss.
DescripciónResumen del trabajo presentado al 37th Annual MidWinter Meeting of the Association for Research in Otolaryngology, celebrado del 22 al 26 de febrero de 2014 en San Diego-California (US).
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