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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. Ca2+-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.<\/jats:p>","DOI":"10.3390\/ijms242015277","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T10:43:10Z","timestamp":1697539390000},"page":"15277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal Degeneration"],"prefix":"10.3390","volume":"24","author":[{"given":"Arianna","family":"Tolone","sequence":"first","affiliation":[{"name":"Cell Death Mechanism Group, Institute for Ophthalmic Research, Eberhard-Karls-Universit\u00e4t T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0890-9780","authenticated-orcid":false,"given":"Wadood","family":"Haq","sequence":"additional","affiliation":[{"name":"Neuroretinal Electrophysiology and Imaging, Institute for Ophthalmic Research, Eberhard-Karls-Universit\u00e4t T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Fachinger","sequence":"additional","affiliation":[{"name":"Biochemistry Department, University of Kassel, 34132 Kassel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanksha","family":"Roy","sequence":"additional","affiliation":[{"name":"PamGene International B.V., 5211 \u2018s-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0368-9846","authenticated-orcid":false,"given":"Sandeep","family":"Kesh","sequence":"additional","affiliation":[{"name":"Institute of Physiology II, University Hospital Jena, Friedrich Schiller University Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4792-131X","authenticated-orcid":false,"given":"Andreas","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Biolog Life Science Institute GmbH & Co. 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