@article {Gaomol.118.112581, author = {Songqi Gao and Tanu Parmar and Grazyna Palczewska and Zhiqian Dong and Marcin Golczak and Krzysztof Palczewski and Beata Jastrzebska}, title = {Protective effect of a locked retinal chromophore analogue against light-induced retinal degeneration}, elocation-id = {mol.118.112581}, year = {2018}, doi = {10.1124/mol.118.112581}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Continuous regeneration of the 11-cis-retinal visual chromophore from all-trans-retinal is critical for vision. Insufficiency of 11-cis-retinal arising from the dysfunction of key proteins involved in its regeneration can impair retinal health, ultimately leading to loss of human sight. Delayed recovery of visual sensitivity and night blindness caused by inadequate regeneration of the visual pigment rhodopsin, are typical early signs of this condition. Excessive concentrations of unliganded, constitutively active opsin and increased levels of all-trans-retinal, and its byproducts in photoreceptors also accelerate retinal degeneration following light exposure. Exogenous 9-cis-retinal iso-chromophore can reduce the toxicity of ligand-free opsin but fails to prevent the buildup of retinoid photoproducts when their clearance is defective in human retinopathies such as Stargardt disease or age-related macular degeneration. Here we evaluated the effect of a locked chromophore analogue, 11-cis-6-membered ring-retinal against bright light-induced retinal degeneration in Abca4-/-Rdh8-/- mice. Using in vivo imaging techniques, optical coherence tomography, scanning laser ophthalmoscopy, and two-photon microscopy, along with in vitro histological analysis of retinal morphology, we found that treatment with 11-cis-6-membered ring-retinal prior to light stimulation prevented rod and cone photoreceptor degradation and preserved functional acuity in these mice. Moreover, additive accumulation of 11-cis-6-membered ring-retinal measured in the eyes of these mice by quantitative liquid chromatography-mass spectrometry indicated stable binding of this retinoid to opsin. Together, these results suggest that eliminating excess of unliganded opsin can prevent light-induced retinal degeneration in Abca4-/-Rdh8-/- mice.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2018/07/17/mol.118.112581}, eprint = {https://molpharm.aspetjournals.org/content/early/2018/07/17/mol.118.112581.full.pdf}, journal = {Molecular Pharmacology} }