Lipophenols as new therapeutics toward retinal degeneration: in vitro and in vivo pharmacological studies

Abstract

Purpose : Dry age-related macular degeneration (AMD) and Stargardt disease are going through a common toxic mechanism caused by carbonyl and oxidative stresses (COS) responsible for the accumulation of a toxic bis-retinoid called A2E, and have currently no treatment. The aim of this work is therefore the evaluation of original lipophenols able to reduce both stress mechanisms involved in photoreceptors degeneration for the development of new therapeutics.

Methods : Preliminary in vitro studies identify a lead alkyl-phloroglucinol-DHA named IP-DHA. This lipophenol was able to reduce carbonyl stress in retina cells caused by all-trans-retinal (atRAL) accumulation. However, its antioxidant properties were still weak and therefore we focused on the design of different families of lipophenol derivatives in order to conserve anti-carbonyl activity and improve antioxidant properties. Based on a rational design we developed and optimized the synthesis of three alkyl-polyphenol derivatives (phloroglucinol, resveratrol and quercetin) linked to docosahexaenoic (DHA) moiety. Different in vitro evaluations have been performed on ARPE-19 cells to analyze anti-COS profile of lipophenols: cytotoxicity assay, anti-carbonyl stress properties and antioxidant activity (ROS production and A2E photo-induced toxicity). The best candidate has been evaluated by i.v. injection in a mouse model of Stargardt disease (ABCA4KO).

Results : For all lipophenols, no toxicity has been observed up to 160 µM on RPE cells. The four derivatives showed equivalent anti-carbonyl stress activity against atRAL. Regarding antioxidant profiles, quercetin derivative (Q-3DHA-7OiP) was the most efficient as at 80 µM it scavenges 50% of ROS and protects 50% of cells exposed to A2E. Treatment of mice affected by light-induced photoreceptor degeneration with Q-3DHA-7OiP preserved integrity and functionality of photoreceptors.

Conclusions : In order to increase antioxidant properties of the IP-DHA lead, we synthesized three original lipophenols. The most promising Q-3DHA-7OiP showed anti-COS properties, and was the most effective in protecting retina cells from light-induced toxicity of A2E. This derivative showed interesting protective effects on ABCA4KO mice. Alkyl-quercetin lipophenol is therefore a promising candidate for the development of new therapeutics for macular degeneration.

This is a 2020 ARVO Annual Meeting abstract.