Isopropyl‐phloroglucinol‐DHA protects outer retinal cells against lethal dose of all‐trans‐retinal

Abstract

In vertebrates, visual perception occurs in the rod and cone photoreceptor outer segments (POS) through visual pigments, G protein-coupled receptors (rhodopsin and cone opsins) consisting of the apoprotein opsin and a prosthetic group, the vitamin A-derived chromophore 11-cis-retinal (11cRAL). 1 The light isomerizes 11cRAL to trans configuration (atRAL) and subsequently elicits the conformational transition within the opsin proteins, followed by the activation of the phototransduction cascade. After photoisomerization of

Preclinical pharmacology of a lipophenol in a mouse model of light-induced retinopathy

“…The isopropyl function of this molecule reinforces the nucleophilic nature of its aromatic ring, and DHA should improve its bioavailability and its capacity to reach the outer retina. Our previous in vitro evaluation of cultured retinal cells has shown that this lipophenol reduces the toxicity of atRAL (anti-carbonyl stress activity) and activates redox enzymes to promote antioxidant defenses 23 . We continued this preclinical evaluation with an in vivo study in mice using a light-induced photoreceptor degeneration model in the context of an Abca4 gene deletion that mimics human STGD1.…”

“…Furthermore, two natural components compose lipophenol: one polyphenolic moiety, an antioxidant compound present in foods, named phloroglucinol, an antispasmodic compound already approved by the FDA (Spasfon®), and DHA, a natural PUFA omega-3 present in food and beneficial for vision. We previously showed that the addition of isopropyl did not amend the low toxicity level of lipophenols 23 . For all of these reasons, the risk of toxicity of lipophenols may be considered low.…”

“…Error bars represent the SD, n = 3. structures) or by the low reactivity of IP-DHA with atRAL owing to the presence of DHA. We recently reported that several enzyme systems responsible for detoxifying ROS in the cell (antioxidant/electrophile response element (ARE/EpRE)-activated enzymes, regulated by the Nrf2/Keap1 pathway 24 ) are activated by IP-DHA 23 . Now, we assume that the clearance of ROS is accomplished mainly through this mechanism.…”

“…Previously, we described the protective effect of a docosahexaenoic acid (DHA) lipophenol conjugate, IP-DHA, on ARPE-19 cells challenged with a toxic concentration of atRAL 22 . More recently, we reported that IP-DHA can reduce the toxicity of atRAL by acting either as an atRAL or ROS scavenger or as an Nrf2-mediated enzyme defense inducer 23 , which mediates the transcription of antioxidant/cytoprotective genes 24 .…”

Polyphenols and Fish Oils for Improving Metabolic Health: A Revision of the Recent Evidence for Their Combined Nutraceutical Effects

“…Over the last five years, esterified phenols with DHA have been studied for the treatment of retinal pathologies characterized by high levels of carbonyl and oxidative stresses, including age-related macular degeneration and Stargardt’s disease. Several lipophenols has been synthetized and tested, such as O-alkylated resorcinol derivatives (phloroglucinol or resveratrol) linked to DHA or lysophosphatidylcholine–DHA [ 23 ], isopropyl-phloroglucinol–DHA [ 101 , 102 , 108 ], quercetin conjugated to DHA [ 103 ], and very recently, a new DHA-quercetin lipophenol [ 104 ]. These investigations reported powerful antioxidant properties and high protection activities against reactive aldehyde all-trans-retinal toxicity and photo-oxidative toxicity and constitute highly promising strategies for the prevention of retinal degeneration.…”