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The PKG Inhibitor CN238 Affords Functional Protection of Photoreceptors and Ganglion Cells against Retinal
Arianna Tolone1, Wadood Haq2, Alexandra Fachinger3
1Cell Death Mechanism Group, Institute for Ophthalmic Research, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany.
Abstract:
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. 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.
Insights
A novel cGMP analogue, CN238, protects both photoreceptors and retinal ganglion cells from degeneration in mouse models of hereditary retinal disease. This protein kinase G (PKG) inhibitor shows broad neuroprotective potential for various retinal and neurodegenerative conditions.
Area of Science:
- Neuroscience
- Ophthalmology
- Molecular Biology
Background:
- Hereditary retinal degeneration (RD) is linked to excessive cGMP signaling in photoreceptors.
- Inhibiting cGMP-dependent protein kinase G (PKG) has previously shown promise in reducing photoreceptor loss in RD models.
Purpose of the Study:
- To investigate the neuroprotective effects of a novel PKG inhibitor, CN238, in mouse models of hereditary retinal degeneration.
- To explore the potential of CN238 in protecting both photoreceptors and retinal ganglion cells.
Main Methods:
- Utilized *rd1* and *rd10* mutant mice to model hereditary retinal degeneration.
- Administered the cGMP analogue CN238 to assess photoreceptor and retinal ganglion cell viability and function.
- Performed Ca2+ imaging on retinal explants to analyze ion channel activity.
Main Results:
- CN238 preserved photoreceptor viability and function in *rd1* and *rd10* mice.
- CN238 protected retinal ganglion cells from axotomy-induced degeneration and maintained their functionality.
- PKG inhibition by CN238 reduced phosphorylation of the Kv1.6 channel and modulated Kv1-channel activity in retinal ganglion cells.
Conclusions:
- PKG inhibitors, such as CN238, demonstrate significant neuroprotective capabilities for both photoreceptors and retinal ganglion cells.
- These findings suggest a broad therapeutic potential for PKG inhibitors in treating retinal diseases and potentially other neurodegenerative disorders.
