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

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.

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.

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

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.

Affiliations

1. University of Tübingen, Department of Otolaryngology, Tübingen Hearing Research Centre (THRC), Molecular Physiology of Hearing, Tübingen, Germany

   • Marlies Knipper
   • , Mirko Jaumann
   •  & Lukas Rüttiger

2. University of Tübingen, Interfaculty Institute of Biochemistry, Tübingen, Germany

   • Robert Feil

3. University of Tübingen, Centre for Ophthalmology, Institute for Ophthalmic Research, Division of Experimental Ophthalmology, Tübingen, Germany

   • Francois Paquet-Durand

4. University of Tübingen, Institute of Physiology II, Tübingen, Germany

   • Jutta Engel

5. Department of Biophysics, Medical Faculty, Saarland University, Homburg, Germany

   • Jutta Engel

6. Department of Pharmacology and Toxicology, University of Tübingen, Institute of Pharmacy, Tübingen, Germany

   • Peter Ruth

7. Bayer HealthCare Pharmaceuticals, Global Drug Discovery - Common Mechanism Research, Pharma Research Centre Wuppertal, Wuppertal, Germany

   • Peter Sandner

Corresponding author

Correspondence to Marlies Knipper.

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