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Philippe Brabet, Aurélie CUBIZOLLE, Céline CRAUSTE, Laurent GUILLOU, Anne-Laure BONNEFONT, Joseph VERCAUTEREN, Thierry DURAND, Christian P Hamel; A phloroglucinol-DHA derivative protects against light-induced retinal degeneration in an Abca4-deficient mouse model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2031.
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we have formerly reported the efficacy of new pharmacological molecules from alkylated phloroglucinol (PG) derivatives conjugated with polyunsaturated fatty acid (PUFAs) to reduce all-trans retinal-induced damages (carbonyl and oxidative stress) in outer retinal cells (Crauste C, EurJOC 2014; Cia D, J Cell Mol. Med. 2016). These encouraging in vitro results drive us to assess therapeutic potential of a leading molecule, Isopropyl-PG-DHA (IP-DHA), to treat an Abca4-deficient mouse model of Stargardt disease.
7-9 weeks old Abca4-deficient 129SvEvBrd albino mice were dark-adapted for one day before pupils were dilated. IP-DHA was complexed to fatty-acid free BSA two hours before injection. IP-DHA was injected into the tail vein within 100 µL BSA 10% suspended in PBS. Five minutes after injection, mice were exposed to white fluorescent light (OSRAM DULUX lamps, 2.4 mW/cm2) for 2 hours in a white plastic bucket and then kept in the dark for 5 days before the visual function and retinal morphology analyses were performed. The number of photoreceptor was determined using histological HES staining and their light responses by full-field ERG. We repeated the same injections and then dosed retinoid of the retina. For this purpose, the light exposure lasted 2 min followed by a dark-adaptation for 1 hour.
IP-DHA is an oil after purification because of its long-chain fatty acid. Therefore, its intravenous administration requires complex with a fatty acid carrier protein in the blood such as albumin. The tail vein injection is the most effective and quick to reach the retina, which does not require anesthesia affecting the visual cycle. The light exposure caused 50-60% photoreceptor loss in non-injected and BSA-injected mice compared to dark-adapted control and IP-DHA enabled to recover 75-80% of intact photoreceptors. A-wave and b-wave amplitudes were fully recovered after IP-DHA injection, while latencies were unchanged by treatment. Rescue of visual function last for at least a month after injection. Both 11-cis and all-trans retinal were partially trapped by IP-DHA.
We demonstrated that IP-DHA protects against retinal degeneration in a mouse model of acute stress induced by light. This effect can be partly due to the trapping of retinaldehydes by IP-DHA. Investigations are under way to study the visual cycle.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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