A Comparative Study of Age-Related Hearing Loss in Wild Type and Insulin-Like Growth Factor I Deficient Mice

Instituto de Investigaciones Biomedicas "Alberto Sols", CSIC-UAM Madrid, Spain.
Frontiers in Neuroanatomy (Impact Factor: 3.54). 06/2010; 4:27. DOI: 10.3389/fnana.2010.00027
Source: PubMed


Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1(-/-) null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1(+/+) and null Igf1(-/-) mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1(-/-) null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1(+/+) wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1(-/-) null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss.

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Available from: Rafael Cediel Algovia
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    • "mples were taken for morphological evaluation . Cochlear samples were processed to obtain 5 µm thick paraffin sections following standard procedures . Cochlear morphology was studied in cresyl - violet ( Fluka ; Sigma Aldrich ) stained sections with an Axiophot Zeiss microscope equipped with an Olympus DP70 digital camera as previously described ( Riquelme et al . , 2010 ) ."
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    ABSTRACT: Excessive exposure to noise damages the principal cochlear structures leading to hearing impairment. Inflammatory and immune responses are central mechanisms in cochlear defensive response to noise but, if unregulated, they contribute to inner ear damage and hearing loss. Transforming growth factor β (TGF-β) is a key regulator of both responses and high levels of this factor have been associated with cochlear injury in hearing loss animal models. To evaluate the potential of targeting TGF-β as a therapeutic strategy for preventing or ameliorating noise-induced hearing loss (NIHL), we studied the auditory function, cochlear morphology, gene expression and oxidative stress markers in mice exposed to noise and treated with TGF-β1 peptidic inhibitors P17 and P144, just before or immediately after noise insult. Our results indicate that systemic administration of both peptides significantly improved both the evolution of hearing thresholds and the degenerative changes induced by noise-exposure in lateral wall structures. Moreover, treatments ameliorated the inflammatory state and redox balance. These therapeutic effects were dose-dependent and more effective if the TGF-β1 inhibitors were administered prior to inducing the injury. In conclusion, inhibition of TGF-β1 actions with antagonistic peptides represents a new, promising therapeutic strategy for the prevention and repair of noise-induced cochlear damage.
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    • "However, in a mouse model of IGF-1 deficiency, that is in IGF-1 knockout mice (Camarero et al., 2001, 2002; Cediel et al., 2006; Riquelme et al., 2010), the causes of SNHL were reported as the loss of spiral ganglion neurons, abnormal myelination of the cochlear nerve, and degeneration of the stria vascularis, based on the results of morphological (Camarero et al., 2001, 2002) and auditory brain stem response studies (Cediel et al., 2006; Riquelme et al., 2010). The stria degeneration becomes apparent from the age of 3 months in IGF-1 knockout mice although the loss of spiral ganglion cells commences from the age of 3 weeks (Camarero et al., 2002; Riquelme et al., 2010). Knocking out of Irs2, a gene encoding an intracellular adaptor molecule of IGF1R, also showed similar inner ear phenotypes to IGF-1 knockout mice (Murillo-Cuesta et al., 2012). "
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    • "Both female and male mice were used; no sex-associated parameters were identified in this study. Acoustic stimulation and auditory evoked potential amplification and recording were performed with TDT System 3™ workstation and the specific software SigGenRP™ and BioSigGenRP™ (Tucker Davis Technologies, Alachua FL 32615), as described previously (Cediel et al., 2006) with the modifications reported in Riquelme et al. (2010). The following parameters were analyzed from waves registered during the ABR tests: auditory thresholds in response to click and tone burst stimuli, peak and interpeak latencies and amplitude-intensity and latency-intensity curves. "
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