Apigenin-7-diglucuronide protects retinas against bright light-induced photoreceptor degeneration through the inhibition of retinal oxidative stress and inflammation

Maintaining levels of nicotinamide adenine dinucleotide (NAD +), a coenzyme critical for cellular energetics and biosynthetic pathways, may be therapeutic in retinal disease because retinal NAD + levels decline during retinal damage and degeneration. The purpose of this study was to investigate whether systemic treatment with nicotinamide riboside (NR), a NAD + precursor that is orally deliverable and well-tolerated by humans, is protective in a mouse model of light-induced retinal degeneration. METHODS. Mice were injected intraperitoneally with vehicle or NR the day before and the morning of exposure to degeneration-inducing levels of light. Retinal function was assessed by electroretinography and in vivo retinal morphology and inflammation was assessed by optical coherence tomography. Post mortem retina sections were assessed for morphology, TUNEL, and inflammatory markers Iba1 and GFAP. Retinal NAD + levels were enzymatically assayed. RESULTS. Exposure to degeneration-inducing levels of light suppressed retinal NAD + levels. Mice undergoing light-induced retinal degeneration exhibited significantly suppressed retinal function, severely disrupted photoreceptor cell layers, and increased apoptosis and inflammation in the outer retina. Treatment with NR increased levels of NAD + in retina and prevented these deleterious outcomes. CONCLUSIONS. This study is the first to report the protective effects of NR treatment in a mouse model of retinal degeneration. The positive outcomes, coupled with human tolerance to NR dosing, suggest that maintaining retinal NAD + via systemic NR treatment should be further explored for clinical relevance.

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“…Similar to what we and others reported previously, 29 , 61 – 63 retinas undergoing LIRD exhibited inflammatory responses ( Figs. 7 , 8 , and 9 ).…”

Section: Discussionsupporting

confidence: 92%

Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration

Zhang

Henneman

Girardot

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Nevertheless, chrysin could facilitate the efficient retinoid cycling between the rod outer segment and the RPE through maintaining optimal levels of visual cycle enzymes in RPE cells, as well as retinoid binding proteins. Several studies have demonstrated that dietary flavonoids attenuate retinal degeneration through deterring the apoptosis of RPE cells and photoreceptors via the inhibition of retinal oxidative stress and inflammation [ 42 , 43 , 44 ]. However, little is known about the protective roles of dietary compounds in the alteration of rod visual cycle components.…”

Section: Discussionmentioning

confidence: 99%

Chrysin Ameliorates Malfunction of Retinoid Visual Cycle through Blocking Activation of AGE-RAGE-ER Stress in Glucose-Stimulated Retinal Pigment Epithelial Cells and Diabetic Eyes

et al. 2018

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Diabetes-associated visual cycle impairment has been implicated in diabetic retinopathy, and chronic hyperglycemia causes detrimental effects on visual function. Chrysin, a naturally occurring flavonoid found in various herbs, has anti-inflammatory, antioxidant, and neuroprotective properties. The goal of the current study was to identify the retinoprotective role of chrysin in maintaining robust retinoid visual cycle-related components. The in vitro study employed human retinal pigment epithelial (RPE) cells exposed to 33 mM of glucose or advanced glycation end products (AGEs) in the presence of 1–20 μM chrysin for three days. In the in vivo study, 10 mg/kg of chrysin was orally administrated to db/db mice. Treating chrysin reversed the glucose-induced production of vascular endothelial growth factor, insulin-like growth factor-1, and pigment epithelium-derived factor (PEDF) in RPE cells. The outer nuclear layer thickness of chrysin-exposed retina was enhanced. The oral gavage of chrysin augmented the levels of the visual cycle enzymes of RPE65, lecithin retinol acyltransferase (LRAT), retinol dehydrogenase 5 (RDH5), and rhodopsin diminished in db/db mouse retina. The diabetic tissue levels of the retinoid binding proteins and the receptor of the cellular retinol-binding protein, cellular retinaldehyde-binding protein-1, interphotoreceptor retinoid-binding protein and stimulated by retinoic acid 6 were restored to those of normal mouse retina. The presence of chrysin demoted AGE secretion and AGE receptor (RAGE) induction in glucose-exposed RPE cells and diabetic eyes. Chrysin inhibited the reduction of PEDF, RPE 65, LRAT, and RDH5 in 100 μg/mL of AGE-bovine serum albumin-exposed RPE cells. The treatment of RPE cells with chrysin reduced the activation of endoplasmic reticulum (ER) stress. Chrysin inhibited the impairment of the retinoid visual cycle through blocking ER stress via the AGE-RAGE activation in glucose-stimulated RPE cells and diabetic eyes. This is the first study demonstrating the protective effects of chrysin on the diabetes-associated malfunctioned visual cycle.

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“…Bright Light Stimulation. Exposure to bright light triggers the expression of marker genes associated with inflammation that is implicated in the pathology of photoreceptors degeneration (Bian M et al, 2017, Rutar M et al, 2015. The activity of flavonoids has been associated with the negative modulation of inflammatory stress markers.…”

Section: Effect Of Flavonoids On the Expression Of Inflammatory Markementioning

confidence: 99%

“…Oxidative stress activates host immune and other defense mechanisms that under prolonged insult exacerbate photoreceptor cell death by promoting exaggerated inflammatory responses (Kohno H et al, 2013, Rashid K et al, 2019. Flavonoids can inhibit the inflammatory reactions by suppressing the expression of pro-inflammatory genes and adhesion molecules implicated in the pathogenesis of retinal degeneration (Bian M et al, 2017, Cao X et al, 2010, Lee M et al, 2017. Indeed, bright light-induced retinal inflammation in Abca4 −/− Rdh8 −/− mice was remarkably suppressed by quercetin and myricetin, which at the molecular level correlated with the reduction of the expression of inflammatory markers.…”

Section: Downloaded Frommentioning

confidence: 99%

Protective Effects of Flavonoids in Acute Models of Light-Induced Retinal Degeneration

Ortega¹,

Parmar²,

Golczak³

et al. 2020

Mol Pharmacol

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Degeneration of photoreceptors caused by excessive illumination, inherited mutations or aging are 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 Abca4 −/− Rdh8 −/− and WT BALB/c mice susceptible to light-induced photoreceptors' degeneration. Using in vivo imaging such as optical coherence tomography, scanning laser ophthalmoscopy and histological 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 HPLC-MS 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 BAX/BCL-2 towards an anti-apoptotic profile. These results were confirmed in photoreceptor-derived 661W cells treated with either H 2 O 2 or all-trans-retinal stressors implicated in the mechanism of retinal degeneration. Altogether, flavonoids could have significant prophylactic value for retinal degenerative diseases.

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Apigenin-7-diglucuronide protects retinas against bright light-induced photoreceptor degeneration through the inhibition of retinal oxidative stress and inflammation

Cited by 19 publications

References 28 publications

Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration

Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration

Chrysin Ameliorates Malfunction of Retinoid Visual Cycle through Blocking Activation of AGE-RAGE-ER Stress in Glucose-Stimulated Retinal Pigment Epithelial Cells and Diabetic Eyes

Protective Effects of Flavonoids in Acute Models of Light-Induced Retinal Degeneration

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