cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function
Noise-induced hearing loss (NIHL) is a prevalent problem in the industrialized world. Now, Lukas Rüttiger and colleagues show that the phosphodiesterase inhibitor vardenafil can prevent NIHL in rats and mice. Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiolo...
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| Veröffentlicht in: | Nature medicine 2012-02, Vol.18 (2), p.252-259 |
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| creator | Jaumann, Mirko Dettling, Juliane Gubelt, Martin Zimmermann, Ulrike Gerling, Andrea Paquet-Durand, François Feil, Susanne Wolpert, Stephan Franz, Christoph Varakina, Ksenya Xiong, Hao Brandt, Niels Kuhn, Stephanie Geisler, Hyun-Soon Rohbock, Karin Ruth, Peter Schlossmann, Jens Hütter, Joachim Sandner, Peter Feil, Robert Engel, Jutta Knipper, Marlies Rüttiger, Lukas |
| description | Noise-induced hearing loss (NIHL) is a prevalent problem in the industrialized world. Now, Lukas Rüttiger and colleagues show that the phosphodiesterase inhibitor vardenafil can prevent NIHL in rats and mice.
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. |
| doi_str_mv | 10.1038/nm.2634 |
| format | Article |
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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.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/nm.2634</identifier><identifier>PMID: 22270721</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/154/436/108 ; 631/80/86 ; 692/699/375 ; 692/700/565 ; Animals ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Care and treatment ; Cellular signal transduction ; Cyclic GMP-Dependent Protein Kinase Type I ; Cyclic GMP-Dependent Protein Kinases - physiology ; Cyclic guanylic acid ; Cyclic Nucleotide Phosphodiesterases, Type 5 - drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 5 - physiology ; Deafness, Noise induced ; Ears & hearing ; Enzyme Activation ; Female ; Genetic aspects ; Global health ; Hair ; Hair cells (Mechanoreceptors) ; Hair Cells, Auditory - metabolism ; Hair Cells, Auditory - physiology ; Hair Cells, Auditory, Inner - metabolism ; Hair Cells, Auditory, Inner - physiology ; Hair Cells, Auditory, Outer - metabolism ; Hair Cells, Auditory, Outer - physiology ; Health hazards ; Hearing loss ; Hearing Loss, Noise-Induced - genetics ; Hearing Loss, Noise-Induced - physiopathology ; Hearing Loss, Noise-Induced - prevention & control ; Imidazoles - pharmacology ; Infectious Diseases ; Metabolic Diseases ; Mice ; Mice, Mutant Strains ; Molecular Medicine ; Neurosciences ; Noise ; Noise - adverse effects ; Phosphodiesterase 5 Inhibitors - pharmacology ; Physiological aspects ; Piperazines - pharmacology ; Poly Adenosine Diphosphate Ribose - biosynthesis ; Poly(ADP-ribose) Polymerases - metabolism ; Rats ; Rats, Wistar ; Signal Transduction - genetics ; Signal Transduction - physiology ; Sulfones - pharmacology ; Triazines - pharmacology ; Up-Regulation - drug effects ; Vardenafil Dihydrochloride</subject><ispartof>Nature medicine, 2012-02, Vol.18 (2), p.252-259</ispartof><rights>Springer Nature America, Inc. 2012</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c578t-364c414018f3e562dc41e8ee735c88a7ace686b350c71bcedbee47d62286335f3</citedby><cites>FETCH-LOGICAL-c578t-364c414018f3e562dc41e8ee735c88a7ace686b350c71bcedbee47d62286335f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nm.2634$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nm.2634$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22270721$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jaumann, Mirko</creatorcontrib><creatorcontrib>Dettling, Juliane</creatorcontrib><creatorcontrib>Gubelt, Martin</creatorcontrib><creatorcontrib>Zimmermann, Ulrike</creatorcontrib><creatorcontrib>Gerling, Andrea</creatorcontrib><creatorcontrib>Paquet-Durand, François</creatorcontrib><creatorcontrib>Feil, Susanne</creatorcontrib><creatorcontrib>Wolpert, Stephan</creatorcontrib><creatorcontrib>Franz, Christoph</creatorcontrib><creatorcontrib>Varakina, Ksenya</creatorcontrib><creatorcontrib>Xiong, Hao</creatorcontrib><creatorcontrib>Brandt, Niels</creatorcontrib><creatorcontrib>Kuhn, Stephanie</creatorcontrib><creatorcontrib>Geisler, Hyun-Soon</creatorcontrib><creatorcontrib>Rohbock, Karin</creatorcontrib><creatorcontrib>Ruth, Peter</creatorcontrib><creatorcontrib>Schlossmann, Jens</creatorcontrib><creatorcontrib>Hütter, Joachim</creatorcontrib><creatorcontrib>Sandner, Peter</creatorcontrib><creatorcontrib>Feil, Robert</creatorcontrib><creatorcontrib>Engel, Jutta</creatorcontrib><creatorcontrib>Knipper, Marlies</creatorcontrib><creatorcontrib>Rüttiger, Lukas</creatorcontrib><title>cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Noise-induced hearing loss (NIHL) is a prevalent problem in the industrialized world. Now, Lukas Rüttiger and colleagues show that the phosphodiesterase inhibitor vardenafil can prevent NIHL in rats and mice.
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.</description><subject>631/154/436/108</subject><subject>631/80/86</subject><subject>692/699/375</subject><subject>692/700/565</subject><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cellular signal transduction</subject><subject>Cyclic GMP-Dependent Protein Kinase Type I</subject><subject>Cyclic GMP-Dependent Protein Kinases - physiology</subject><subject>Cyclic guanylic acid</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - drug effects</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - physiology</subject><subject>Deafness, Noise induced</subject><subject>Ears & hearing</subject><subject>Enzyme Activation</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Global 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(NIHL) is a prevalent problem in the industrialized world. Now, Lukas Rüttiger and colleagues show that the phosphodiesterase inhibitor vardenafil can prevent NIHL in rats and mice.
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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>22270721</pmid><doi>10.1038/nm.2634</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2012-02, Vol.18 (2), p.252-259 |
| issn | 1078-8956 1546-170X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1315623963 |
| source | MEDLINE; Springer Online Journals; Nature Research |
| subjects | 631/154/436/108 631/80/86 692/699/375 692/700/565 Animals Biomedical and Life Sciences Biomedicine Cancer Research Care and treatment Cellular signal transduction Cyclic GMP-Dependent Protein Kinase Type I Cyclic GMP-Dependent Protein Kinases - physiology Cyclic guanylic acid Cyclic Nucleotide Phosphodiesterases, Type 5 - drug effects Cyclic Nucleotide Phosphodiesterases, Type 5 - physiology Deafness, Noise induced Ears & hearing Enzyme Activation Female Genetic aspects Global health Hair Hair cells (Mechanoreceptors) Hair Cells, Auditory - metabolism Hair Cells, Auditory - physiology Hair Cells, Auditory, Inner - metabolism Hair Cells, Auditory, Inner - physiology Hair Cells, Auditory, Outer - metabolism Hair Cells, Auditory, Outer - physiology Health hazards Hearing loss Hearing Loss, Noise-Induced - genetics Hearing Loss, Noise-Induced - physiopathology Hearing Loss, Noise-Induced - prevention & control Imidazoles - pharmacology Infectious Diseases Metabolic Diseases Mice Mice, Mutant Strains Molecular Medicine Neurosciences Noise Noise - adverse effects Phosphodiesterase 5 Inhibitors - pharmacology Physiological aspects Piperazines - pharmacology Poly Adenosine Diphosphate Ribose - biosynthesis Poly(ADP-ribose) Polymerases - metabolism Rats Rats, Wistar Signal Transduction - genetics Signal Transduction - physiology Sulfones - pharmacology Triazines - pharmacology Up-Regulation - drug effects Vardenafil Dihydrochloride |
| title | cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T19%3A54%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=cGMP-Prkg1%20signaling%20and%20Pde5%20inhibition%20shelter%20cochlear%20hair%20cells%20and%20hearing%20function&rft.jtitle=Nature%20medicine&rft.au=Jaumann,%20Mirko&rft.date=2012-02-01&rft.volume=18&rft.issue=2&rft.spage=252&rft.epage=259&rft.pages=252-259&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/nm.2634&rft_dat=%3Cgale_proqu%3EA280558731%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1018986290&rft_id=info:pmid/22270721&rft_galeid=A280558731&rfr_iscdi=true |