Activation of IGF1 Signaling in the Cochlea Induces the Transcription of Its Mediators During the Protection of Cochlear Hair Cells Against Aminoglycoside

Hypothesis: Transcription of the Erk and Akt genes and phosphorylation of their products are promoted by insulin-like growth factor 1 (IGF1) during hair cell protection. Background: IGF1 protects mammalian hair cells in animal models from various types of damage, including aminoglycoside. Moreover, clinical trials have revealed that IGF1 was effective for idiopathic sudden sensorineural hearing loss. In this process, activation of the downstream of IGF1 signaling, including the phosphorylation of extracellular signal-regulated kinase (ERK) and AKT proteins, is involved. However, the regulation of IGF1 signaling mediators at the transcriptional level has not been studied. Methods: We used a neomycin damage model on neonatal mouse cochlear explant culture. Explants established from neonatal mice were treated with either neomycin alone or neomycin and IGF1. The expression levels of IGF1 signaling mediator genes, Akt1 , Mapk3 , and Mapk1 , in the explants were compared using quantitative reverse transcriptase-polymerase chain reaction at several time points. Inhibitors of IGF1 signaling were added to confirm that this observation was dependent on IGF1 signaling. Results: The expression levels of all genes tested were significantly upregulated in neomycin+IGF1 treatment samples ( p < 0.0001, analysis of variance [ANOVA]). Addition of inhibitors of IGF1 signaling significantly attenuated the upregulation of expression ( p < 0.0001, ANOVA). Conclusions: IGF1 treatment upregulates the expression of its mediator genes during the protection of hair cells against aminoglycoside. The regulation of mediator gene expression may serve as a novel treatment for sensorineural hearing loss.