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

Abstract

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.

New lipophenols prevent carbonyl and oxidative stresses involved in macular degeneration

“…The DHA analogue (LEAD B) was selected for further in vivo evaluations due to several benefits of this omega-3 lipid: i) the high proportion of DHA in the membrane of photoreceptor outer segments, ii) its ability to reach the retina through PUFA transports [27]; iii) recent data showing that dietary supplementation with high doses of DHA/EPA significantly improves the visual acuity of AMD patients [25]; and iv) the report that specific oxidative metabolites of DHA (Neuroprotectin D1) protect RPE cells against oxidative stress [28]. Intravenous administration of LEAD B allowed photoreceptor protection against acute light-induced degeneration in a mouse model used for the development of novel therapeutics for Stargardt disease (Abca4 − /− mice) [29,30]. Despite interesting preliminary in vivo protection observed using LEAD B, this phloroglucinol derivative lacks efficiency to reduce ROS production and cellular oxidative stress.…”

Formulation and Evaluation of SNEDDS Loaded with Original Lipophenol for the Oral Route to Prevent Dry AMD and Stragardt’s Disease

“…Finally, to promote the targeting of the molecule to the outer retina, we also grafted docosahexaenoic acid (DHA, C22:4 n-3), a polyunsaturated fatty acid that is localized in the photoreceptor disc membrane and that is known to have several benefits for retina protection and function [ 27 ]. As the mechanism of action for IP-DHA has been previously discussed [ 8 , 28 ], this present work focused on the impact of the IP-DHA features on its resulting activity based on photoreceptor protection. Thus, the study then led to the development of the formulation best suited for oral delivery.…”

“…In vitro experiments on retinal cells demonstrated the absence of the toxicity of IP-DHA, the protective effect of the drug after the induction of oxidative and carbonyl stress, and the importance of the alkyl and the omega-3 chains for efficient cell protection [ 7 ]. This drug has also proven its efficacy in vivo on an ABCA4KO ( −/− ) mouse model via an intravenous route (the protection of photoreceptors in the range of 80–85%), and did not affect the retinoid visual cycle [ 8 ]. The next step for the development of the treatment is therefore to formulate IP-DHA for oral route administration, to evaluate this formulation in vitro in terms of stability, drug loading, and droplet size, and to prove its in vivo efficacy after inducing retinal degeneration with acute and chronic light stress on ABCA4KO and BALB/c mouse models.…”

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.…”