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cGMP-Prkg1 signaling PDE5 inhibition shelter cochlear hair cells and hearing function

Background

Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events.

Results

We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase.

Conclusion

These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.

Acknowledgements

This work was supported by the Marie Curie Research Training Network CavNET MRTN-CT-2006-035367, the Royal National Institute for Deaf People (RNID) G54_Rüttiger, the Hahn Stiftung (Index AG), the Graduate Program of the University of Tübingen, the Landesgraduiertenförderung Baden-Württemberg, Germany, the Kerstan Stiftung and Deutsche Forschungsgemeinschaft (DFG) PA1751/1-1 and DFG Fe 438/2, the Fortüne Program of the University Tübingen.

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Correspondence to Marlies Knipper.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Knipper, M., Jaumann, M., Paquet-Durand, F. et al. cGMP-Prkg1 signaling PDE5 inhibition shelter cochlear hair cells and hearing function. BMC Pharmacol Toxicol 14, O27 (2013). https://doi.org/10.1186/2050-6511-14-S1-O27

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Keywords

  • Hearing Loss
  • Hair Cell
  • Phosphodiesterase
  • PDE5 Inhibition
  • Spiral Ganglion