New lipophenols prevent carbonyl and oxidative stresses involved in macular degeneration (original) (raw)
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New Lipophenol Antioxidants Reduce Oxidative Damage in Retina Pigment Epithelial Cells
Antioxidants
Age-related macular degeneration (AMD) is a multifactorial pathology and its progression is exacerbated by oxidative stress. Oxidation and photo-oxidation reactions modify lipids in retinal cells, contribute to tissue injury, and lead to the formation of toxic adducts. In particular, autofluorescent pigments such as N-retinylidene-N-retinylethanolamine (A2E) accumulate as lipofuscin in retinal pigment epithelial cells, contribute to the production of additional reactive oxygen species (ROS), and lead to cell degeneration. In an effort to develop efficient antioxidants to reduce damage caused by lipid oxidation, various natural polyphenols were structurally modified to increase their lipophilicity (lipophenols). In this study, resveratrol, phloroglucinol, quercetin and catechin were selected and conjugated to various polyunsaturated fatty acids (PUFAs) using classical chemical strategies or enzymatic reactions. After screening for cytotoxicity, the capacity of the synthesized lipophe...
Journal of cellular and molecular medicine, 2016
Among retinal macular diseases, the juvenile recessive Stargardt disease and the age-related degenerative disease arise from carbonyl and oxidative stresses (COS). Both stresses originate from an accumulation of all-trans-retinal (atRAL) and are involved in bisretinoid formation by condensation of atRAL with phosphatidylethanolamine (carbonyl stress) in the photoreceptor and its transformation into lipofuscin bisretinoids (oxidative stress) in the retinal pigment epithelium (RPE). As atRAL and bisretinoid accumulation contribute to RPE and photoreceptor cell death, our goal is to select powerful chemical inhibitors of COS. Here, we describe that phloroglucinol, a natural phenolic compound having anti-COS properties, protects both rat RPE and mouse photoreceptor primary cultures from atRAL-induced cell death and reduces hydrogen peroxide (H2 O2 )-induced damage in RPE in a dose-dependent manner. Mechanistic analyses demonstrate that the protective effect encompasses decrease in atRAL...
Preclinical pharmacology of a lipophenol in a mouse model of light-induced retinopathy
Experimental & Molecular Medicine
Environmental light has deleterious effects on the outer retina in human retinopathies, such as ABCA4-related Stargardt's disease and dry age-related macular degeneration. These effects involve carbonyl and oxidative stress, which contribute to retinal cell death and vision loss. Here, we used an albino Abca4 −/− mouse model, the outer retina of which shows susceptibility to acute photodamage, to test the protective efficacy of a new polyunsaturated fatty acid lipophenol derivative. Anatomical and functional analyses demonstrated that a single intravenous injection of isopropyl-phloroglucinol-DHA, termed IP-DHA, dose-dependently decreased light-induced photoreceptor degeneration and preserved visual sensitivity. This protective effect persisted for 3 months. IP-DHA did not affect the kinetics of the visual cycle in vivo or the activity of the RPE65 isomerase in vitro. Moreover, IP-DHA administered by oral gavage showed significant protection of photoreceptors against acute light damage. In conclusion, short-term tests in Abca4-deficient mice, following single-dose administration and light exposure, identify IP-DHA as a therapeutic agent for the prevention of retinal degeneration.
Archives of Toxicology, 2019
Age-related macular degeneration (AMD) is a late-onset retinal disease and the leading cause of central vision loss in the elderly. Degeneration of retinal pigment epithelial cells (RPE) is a crucial contributing factor responsible for the onset and progression of AMD. The toxic fluorophore N-retinyl-N-retinylidene ethanolamine (A2E), a major lipofuscin component, accumulates in RPE cells with age. Phytochemicals with antioxidant properties may have a potential role in both the prevention and treatment of this age-related ocular disease. Particularly, there is an increased interest in the therapeutic effects of resveratrol (RSV), a naturally occurring polyphenol (3,4′,5-trihydroxystilbene). However, the underlying mechanism of the RSV antioxidative effect in ocular diseases has not been well explored. We hypothesized that this bioactive compound may have beneficial effects for AMD. To this end, to investigate the potential profits of RSV against A2E-provoked oxidative damage, we used human RPE cell line (ARPE-19). RSV (25 µM) attenuates the cytotoxicity and the typical morphological characteristics of apoptosis observed in 25 µM A2E-laden cells. RSV pretreatment strengthened cell monolayer integrity through the preservation of the transepithelial electrical resistance and reduced the fluorescein isothiocyanate (FITC)-dextran diffusion rate as well as cytoskeleton architecture. In addition, RSV exhorts protective effects against A2E-induced modifications in the intracellular redox balance. Finally, RSV also prevented A2E-induced mitochondrial network fragmentation. These findings reinforce the idea that RSV represents an attractive bioactive for therapeutic intervention against ocular diseases associated with oxidative stress such as AMD.
Isopropyl‐phloroglucinol‐DHA protects outer retinal cells against lethal dose of all‐trans‐retinal
Journal of Cellular and Molecular Medicine, 2020
All‐trans‐retinal (atRAL) is a highly reactive carbonyl specie, known for its reactivity on cellular phosphatidylethanolamine in photoreceptor. It is generated by photoisomerization of 11‐cis‐retinal chromophore linked to opsin by the Schiff's base reaction. In ABCA4‐associated autosomal recessive Stargardt macular dystrophy, atRAL results in carbonyl and oxidative stress, which leads to bisretinoid A2E, accumulation in the retinal pigment epithelium (RPE). This A2E‐accumulation presents as lipofuscin fluorescent pigment, and its photooxidation causes subsequent damage. Here we describe protection against a lethal dose of atRAL in both photoreceptors and RPE in primary cultures by a lipidic polyphenol derivative, an isopropyl‐phloroglucinol linked to DHA, referred to as IP‐DHA. Next, we addressed the cellular and molecular defence mechanisms in commonly used human ARPE‐19 cells. We determined that both polyunsaturated fatty acid and isopropyl substituents bond to phloroglucinol ...
Oxidative Medicine and Cellular Longevity
Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by degeneration and loss of photoreceptors and retinal pigment epithelium (RPE) cells with oxidative stress playing a role in its pathology. Although systematic reviews do not support the protective role of diet rich in antioxidants against AMD, dietary polyphenols (DPs) have been reported to have beneficial effects on vision. Some of them, such as quercetin and cyanidin-3-glucoside, can directly scavenge reactive oxygen species (ROS) due to the presence of two hydroxyl groups in their B ring structure. Apart from direct ROS scavenging, DPs can lower oxidative stress in several other pathways. Many DPs induce NRF2 (nuclear factor, erythroid 2-like 2) activation and expression of phase II enzymes that are under transcriptional control of this factor. DPs can inhibit A2E photooxidation in RPE cells, which is a source of oxidative stress. Anti-inflammatory action of DPs in RPE cells is associated ...
Bioorganic & Medicinal Chemistry, 2008
The Piper betel phenolics, allylpyrocatechol (APC) and chavibetol (CHV), were found to protect photosensitization-mediated lipid peroxidation (LPO) of rat liver mitochondria effectively, APC being significantly more potent. The better activity of APC vis-à -vis CHV could be attributed to its higher reactivity with 1 O 2 , as revealed from the rate constant values of 1 O 2 quenching by the respective phenolics. APC also prevented the detrimental effects of the Type II photosensitization-induced toxicity to mouse fibroblast L929 cells. The results suggest that APC may play an important role in protecting biological systems against damage, by eliminating 1 O 2 generated from certain endogenous photosensitizers.