期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 20, 页码 -出版社
MDPI
DOI: 10.3390/ijms242015277
关键词
neuroprotection; retinitis pigmentosa; cGMP; PKG or PKG1; Kv1.3; Kv1.6; functional vision preservation; ERG; cGMP analogues or PKG inhibitors
The study found that CN238, a cGMP analogue and PKG inhibitor, can protect photoreceptors and retinal ganglion cells from degeneration, indicating its potential for treating retinal and neurodegenerative diseases.
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.
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