Abstract

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.

Links

Publisher Full Text

Authors

Jaumann M, Dettling J, Gubelt M, Zimmermann U, Gerling A, Paquet-Durand F, Feil S, Wolpert S, Franz C, Varakina K, Xiong H, Brandt N, Kuhn S, Geisler HS, Rohbock K, Ruth P, Schlossmann J, Hütter J, Sandner P, Feil R, Engel J, Knipper M, Rüttiger L

Institution

University of Tübingen, Department of Otolaryngology, Tübingen Hearing Research Centre, Molecular Physiology of Hearing, Tübingen, Germany.

Source

Nature medicine 18:2 2012 Feb pg 252-9

MeSH

Animals
Cyclic GMP-Dependent Protein Kinases
Cyclic Nucleotide Phosphodiesterases, Type 5
Enzyme Activation
Female
Hair Cells, Auditory
Hair Cells, Auditory, Inner
Hair Cells, Auditory, Outer
Hearing Loss, Noise-Induced
Imidazoles
Mice
Mice, Mutant Strains
Noise
Phosphodiesterase 5 Inhibitors
Piperazines
Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Rats
Rats, Wistar
Signal Transduction
Sulfones
Triazines
Up-Regulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22270721