Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro.

BACKGROUND: Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, are commonly used as cholesterol-lowering drugs. During the past decade, evidence has emerged that statins also have neuroprotective effects. Research in the retina has shown that simvastatin, a commonly used statin, increases Akt phosphorylation in vivo, indicating that the PI3K/Akt pathway contributes to the protective effects achieved. While research about neuroprotective effects have been conducted in several systems, the effects of statins on the inner ear are largely unknown. RESULTS: We evaluated whether the 3-hydroxy-3-methylglutaryl-coenzyme A reductase is present within the rat cochlea and whether simvastatin is able to protect auditory hair cells from gentamicin-induced apoptotic cell death in a in vitro mouse model. Furthermore, we evaluated whether simvastatin increases Akt phosphorylation in the organ of Corti. We detected 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in organ of Corti, spiral ganglion, and stria vascularis by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, we observed a dose-dependent and significant reduction of hair cell loss in organs of Corti treated with simvastatin in addition to gentamicin, as compared to samples treated with gentamicin alone. The protective effect of simvastatin was reversed by addition of mevalonate, a downstream metabolite blocked by simvastatin, demonstrating the specificity of protection. Finally, Western blotting showed an increase in organ of Corti Akt phosphorylation after simvastatin treatment in vitro. CONCLUSION: These results suggest a neuroprotective effect of statins in the inner ear, mediated by reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase metabolism and Akt activation.

T-cadherin in the mammalian cochlea.

OBJECTIVES/HYPOTHESIS: Cadherins are a superfamily of transmembrane glycoproteins, which mediate calcium-dependent intercellular adhesions. T-cadherin is an atypical member of the cadherin family in regard to its structure; it acts as a signalling receptor rather than an adhesion molecule. In this study we examine the role of T-cadherin in the mammalian cochlea. STUDY DESIGN: This study investigated the expression of T-cadherin in the inner ear under physiologic and pathologic conditions. METHODS: Expression of T-cadherin in the rat cochlea was analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR), real-time RT-PCR, Western blot, and immunohistochemistry. RESULTS: We detected T-cadherin mRNA expression in three different components in the cochlea of postnatal mouse, namely the organ of Corti (OC), the spiral ganglion (SG), and the stria vascularis (SV). The SG and SV showed a higher T-cadherin mRNA level than the OC. T-cadherin protein was detected by Western blotting in the OC, SG, and SV. Immunofluorescence microscopy of adult mouse cochlea revealed the presence of T-cadherin in the apical parts of the inner and outer hair cells as well as in the SV and SG. OCs treated with gentamicin for 3, 6, or 12 hours did not show any change in T-cadherin gene expression compared to control explants maintained in culture medium alone. CONCLUSIONS: T-cadherin is expressed within the cochlea. T-cadherin seems to have a wide variety of functions in the inner ear, ranging from mechanical functions to functions in response to hair cell damage and loss.