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Protective Effects of Flavonoids in Acute Models of Light-Induced Retinal Degeneration
Joseph T Ortega1, Tanu Parmar1, Marcin Golczak1
1Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Abstract:
Degeneration of photoreceptors caused by excessive illumination, inherited mutations, or aging is the principal pathology of blinding diseases. Pharmacological compounds that stabilize the visual receptor rhodopsin and modulate the cellular pathways triggering death of photoreceptors could avert this pathology. Interestingly, flavonoids can modulate the cellular processes, such as oxidative stress, inflammatory responses, and apoptosis, that are activated during retinal degeneration. As we found previously, flavonoids also bind directly to unliganded rod opsin, enhancing its folding, stability, and regeneration. In addition, flavonoids stimulate rhodopsin gene expression. Thus, we evaluated the effect of two main dietary flavonoids, quercetin and myricetin, in ATP-binding cassette subfamily A member 4 /retinol dehydrogenase 8 and wild-type BALB/c mice susceptible to light-induced photoreceptor degeneration. Using in vivo imaging, such as optical coherence tomography, scanning laser ophthalmoscopy, and histologic assessment of retinal morphology, we found that treatment with these flavonoids prior to light insult remarkably protected retina from deterioration and preserved its function. Using high-performance liquid chromatography-mass spectrometry analysis, we detected these flavonoids in the eye upon their intraperitoneal administration. The molecular events associated with the protective effect of quercetin and myricetin were related to the elevated expression of photoreceptor-specific proteins, rhodopsin and cone opsins, decreased expression of the specific inflammatory markers, and the shift of the equilibrium between cell death regulators BCL2-associated X protein (BAX) and B-cell lymphoma 2 toward an antiapoptotic profile. These results were confirmed in photoreceptor-derived 661W cells treated with either H2O2 or all-trans-retinal stressors implicated in the mechanism of retinal degeneration. Altogether, flavonoids could have significant prophylactic value for retinal degenerative diseases. SIGNIFICANCE STATEMENT: Flavonoids commonly present in food exhibit advantageous effects in blinding diseases. They bind to and stabilize unliganded rod opsin, which in excess accelerates degenerative processes in the retina. Additionally, flavonoids enhance the expression of the visual receptors, rod and cone opsins; inhibit the inflammatory reactions; and induce the expression of antiapoptotic markers in the retina, preventing the degeneration in vivo. Thus, flavonoids could have a prophylactic value for retinal degenerative diseases.
Insights
Dietary flavonoids like quercetin and myricetin protect against blinding diseases by stabilizing rhodopsin and reducing photoreceptor cell death. These compounds show prophylactic value for retinal degenerative diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Photoreceptor degeneration underlies major blinding diseases.
- Dietary flavonoids modulate cellular processes implicated in retinal degeneration, including oxidative stress, inflammation, and apoptosis.
- Flavonoids bind to and stabilize unliganded rod opsin, enhancing its folding and regeneration, and also stimulate rhodopsin gene expression.
Purpose of the Study:
- To evaluate the protective effects of dietary flavonoids, quercetin and myricetin, against light-induced photoreceptor degeneration in mice.
- To investigate the molecular mechanisms underlying the observed protective effects of these flavonoids in the retina.
Main Methods:
- Treatment with quercetin and myricetin was administered to mice susceptible to light-induced photoreceptor degeneration.
- In vivo imaging techniques (optical coherence tomography, scanning laser ophthalmoscopy) and histologic assessment were used to evaluate retinal morphology and function.
- High-performance liquid chromatography-mass spectrometry (HPLC-MS) was employed to detect flavonoid presence in the eye.
- Photoreceptor-derived 661W cells were used to confirm findings under oxidative and retinoid stress.
Main Results:
- Flavonoid treatment significantly protected the retina from light-induced degeneration and preserved visual function.
- Detected presence of quercetin and myricetin in the eye post-administration.
- Molecular analysis revealed elevated expression of photoreceptor proteins (rhodopsin, cone opsins), decreased inflammatory markers, and an antiapoptotic shift (BCL2/BAX ratio).
- Results were corroborated in vitro using 661W cells exposed to H2O2 or all-trans-retinal.
Conclusions:
- Dietary flavonoids, quercetin and myricetin, demonstrate significant prophylactic potential against retinal degenerative diseases.
- Their protective mechanisms involve stabilizing rhodopsin, enhancing visual receptor expression, reducing inflammation, and promoting cell survival.
- Flavonoids represent a promising therapeutic strategy for preventing vision loss in blinding conditions.
