title: cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.
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.
authors.affiliation: University of Tübingen, Department of Otolaryngology, Tübingen Hearing Research Centre, Molecular Physiology of Hearing, Tübingen, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Jaumann
authors.forename: Juliane
authors.initials: J
authors.lastname: Dettling
authors.forename: Martin
authors.initials: M
authors.lastname: Gubelt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zimmermann
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerling
authors.forename: François
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: Susanne
authors.initials: S
authors.lastname: Feil
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolpert
authors.forename: Christoph
authors.initials: C
authors.lastname: Franz
authors.forename: Ksenya
authors.initials: K
authors.lastname: Varakina
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.forename: Niels
authors.initials: N
authors.lastname: Brandt
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kuhn
authors.forename: Hyun-Soon
authors.initials: HS
authors.lastname: Geisler
authors.forename: Karin
authors.initials: K
authors.lastname: Rohbock
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: Jens
authors.initials: J
authors.lastname: Schlossmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Hütter
authors.forename: Peter
authors.initials: P
authors.lastname: Sandner
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Jutta
authors.initials: J
authors.lastname: Engel
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.forename: Lukas
authors.initials: L
authors.lastname: Rüttiger
mesh_terms: D000818:Animals; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000502:physiology*; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism / Q000502:physiology; D018072:Hair Cells, Auditory, Outer / Q000378:metabolism / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009622:Noise / Q000009:adverse effects; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000069058:Vardenafil Dihydrochloride
chemical_list: D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D013450:Sulfones; D014227:Triazines; D011064:Poly Adenosine Diphosphate Ribose; D000069058:Vardenafil Dihydrochloride; D011065:Poly(ADP-ribose) Polymerases; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5