cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function

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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.

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Figure 1: Prkg1 and Pde5 expression in the cochlea.
Figure 2: Pde5 and Prkg1 localization in the cochlea.
Figure 3: Immunohistochemical staining for Kcnq4 protein in control and Prkg1-deficient mice.
Figure 4: Vardenafil treatment during NIHL.
Figure 5: IHC and OHC preservation after noise trauma and treatment with vardenafil.
Figure 6: Parp activity after vardenafil treatment.


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We thank S. Kasperek for excellent technical assistance and R. Panford-Walsh for proofreading the manuscript. 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.

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M.J., F.P.-D., P.R., R.F., J.E., M.K. and L.R. designed the research. M.J., J.D., M.G., U.Z., S.W., K.V., H.X. and L.R. performed experiments. C.F. and M.K. conducted immunofluorescent microscopy and image analyses. H.-S.G. and K.R. provided technical support. A.G. and S.F. prepared mutant mice, designed primers and generated antibodies. J.E., N.B. and S.K. isolated hair cell tissues and contributed to the RT-PCR. P.R. and J.S. designed protein detection methods and provided antibodies for histology. J.H. and P.S. established drug application protocols in rats and provided the Pde5 inhibitor. M.K. and L.R. planned and supervised the project. M.J., F.P.-D., R.F., J.E., M.K. and L.R. wrote the manuscript, which was revised by all authors.

Correspondence to Lukas Rüttiger.

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Jaumann, M., Dettling, J., Gubelt, M. et al. cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function. Nat Med 18, 252–259 (2012) doi:10.1038/nm.2634

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