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The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration

Hereditary retinal degeneration (RD) is often associated with excessive cGMP signalling in photoreceptors. Previous research has shown that inhibition of cGMP-dependent protein kinase G (PKG) can reduce photoreceptor loss in two different RD animal models. In this study, we identified a PKG inhibito...

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Autores principales: Tolone, Arianna, Haq, Wadood, Fachinger, Alexandra, Roy, Akanksha, Kesh, Sandeep, Rentsch, Andreas, Wucherpfennig, Sophie, Zhu, Yu, Groten, John, Schwede, Frank, Tomar, Tushar, Herberg, Friedrich W., Nache, Vasilica, Paquet-Durand, François
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10607377/
https://www.ncbi.nlm.nih.gov/pubmed/37894958
http://dx.doi.org/10.3390/ijms242015277
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author Tolone, Arianna
Haq, Wadood
Fachinger, Alexandra
Roy, Akanksha
Kesh, Sandeep
Rentsch, Andreas
Wucherpfennig, Sophie
Zhu, Yu
Groten, John
Schwede, Frank
Tomar, Tushar
Herberg, Friedrich W.
Nache, Vasilica
Paquet-Durand, François
author_facet Tolone, Arianna
Haq, Wadood
Fachinger, Alexandra
Roy, Akanksha
Kesh, Sandeep
Rentsch, Andreas
Wucherpfennig, Sophie
Zhu, Yu
Groten, John
Schwede, Frank
Tomar, Tushar
Herberg, Friedrich W.
Nache, Vasilica
Paquet-Durand, François
author_sort Tolone, Arianna
collection PubMed
description Hereditary retinal degeneration (RD) is often associated with excessive cGMP signalling in photoreceptors. Previous research has shown that inhibition of cGMP-dependent protein kinase G (PKG) can reduce photoreceptor loss in two different RD animal models. In this study, we identified a PKG inhibitor, the cGMP analogue CN238, which preserved photoreceptor viability and functionality in rd1 and rd10 mutant mice. Surprisingly, in explanted retinae, CN238 also protected retinal ganglion cells from axotomy-induced retrograde degeneration and preserved their functionality. Furthermore, kinase activity-dependent protein phosphorylation of the PKG target Kv1.6 was reduced in CN238-treated rd10 retinal explants. Ca(2+)-imaging on rd10 acute retinal explants revealed delayed retinal ganglion cell repolarization with CN238 treatment, suggesting a PKG-dependent modulation of Kv1-channels. Together, these results highlight the strong neuroprotective capacity of PKG inhibitors for both photoreceptors and retinal ganglion cells, illustrating their broad potential for the treatment of retinal diseases and possibly neurodegenerative diseases in general.
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spelling pubmed-106073772023-10-28 The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration Tolone, Arianna Haq, Wadood Fachinger, Alexandra Roy, Akanksha Kesh, Sandeep Rentsch, Andreas Wucherpfennig, Sophie Zhu, Yu Groten, John Schwede, Frank Tomar, Tushar Herberg, Friedrich W. Nache, Vasilica Paquet-Durand, François Int J Mol Sci Article Hereditary retinal degeneration (RD) is often associated with excessive cGMP signalling in photoreceptors. Previous research has shown that inhibition of cGMP-dependent protein kinase G (PKG) can reduce photoreceptor loss in two different RD animal models. In this study, we identified a PKG inhibitor, the cGMP analogue CN238, which preserved photoreceptor viability and functionality in rd1 and rd10 mutant mice. Surprisingly, in explanted retinae, CN238 also protected retinal ganglion cells from axotomy-induced retrograde degeneration and preserved their functionality. Furthermore, kinase activity-dependent protein phosphorylation of the PKG target Kv1.6 was reduced in CN238-treated rd10 retinal explants. Ca(2+)-imaging on rd10 acute retinal explants revealed delayed retinal ganglion cell repolarization with CN238 treatment, suggesting a PKG-dependent modulation of Kv1-channels. Together, these results highlight the strong neuroprotective capacity of PKG inhibitors for both photoreceptors and retinal ganglion cells, illustrating their broad potential for the treatment of retinal diseases and possibly neurodegenerative diseases in general. MDPI 2023-10-17 /pmc/articles/PMC10607377/ /pubmed/37894958 http://dx.doi.org/10.3390/ijms242015277 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tolone, Arianna
Haq, Wadood
Fachinger, Alexandra
Roy, Akanksha
Kesh, Sandeep
Rentsch, Andreas
Wucherpfennig, Sophie
Zhu, Yu
Groten, John
Schwede, Frank
Tomar, Tushar
Herberg, Friedrich W.
Nache, Vasilica
Paquet-Durand, François
The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration
title The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration
title_full The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration
title_fullStr The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration
title_full_unstemmed The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration
title_short The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration
title_sort pkg inhibitor cn238 affords functional protection of photoreceptors and ganglion cells against retinal degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10607377/
https://www.ncbi.nlm.nih.gov/pubmed/37894958
http://dx.doi.org/10.3390/ijms242015277
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