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Open Access Highly Accessed Research article

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

Yves Brand124, Cristian Setz12, Soledad Levano12, Alwin Listyo12, Eduardo Chavez4, Kwang Pak3, Michael Sung4, Vesna Radojevic12, Allen F Ryan345 and Daniel Bodmer12*

  • * Corresponding author: Daniel Bodmer dbodmer@uhbs.ch

  • † Equal contributors

Author affiliations

1 Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland

2 Clinic of Otolaryngology, Head and Neck Surgery, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland

3 San Diego VA Medical Center, 3350 La Jolla Village Drive, La Jolla, CA 92037, USA

4 Surgery/Otolaryngology, UCSD School of Medicine, 9500 Gilman Drive MC0666, La Jolla, CA 92093-0666, USA

5 Neurosciences Departments, UCSD School of Medicine, 9500 Gilman Drive MC0666, La Jolla, CA 92093-0666, USA

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Citation and License

BMC Neuroscience 2011, 12:114  doi:10.1186/1471-2202-12-114

Published: 14 November 2011

Abstract

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.