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Martin Rudolf, Armin Mohi, Zouhair Aherrahrou, Salvatore Grisanti, Yoko Miura; Oral administration of Apolipoprotein A-I mimetic peptide D-4F reduces lipid accumulation in murine Bruch’s membrane (BrM). Invest. Ophthalmol. Vis. Sci. 2013;54(15):1714.
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© ARVO (1962-2015); The Authors (2016-present)
Neutral lipid accumulation in BrM is a major age change in the eye and an important factor for the development of age-related macular degeneration (AMD). ApolipoproteinA-I mimetic peptides like D-4F, primarily developed to remove lipids from atherosclerotic lesions, demonstrated already a significant reduction of BrM lipids after intravitreal injection (Rudolf et al., IOVS 2010, 51: Abstract 2984). Here we report the effect of oral administered D-4F on murine BrM lipid deposits and atherosclerotic aorta lesions in an established atherosclerosis mouse model.
Forty 11 months old ApoEnull mice received D-4F orally with their daily drinking water (50 µg/ml). The animals were sacrificed at 4 different time points after treatment start (4, 8, 12, and 16 weeks) and serum level of HLDC, LDLC and triglyceride was determined. As controls ten animals received only regular water and were sacrificed at treatment start (baseline). All eyes were enucleated, processed to BrM wholemounts, stained with the fluorescent dye PFO/D4-GFP for esterified cholesterol, and evaluated for the BrM lipid content semiquantitatively. Atherosclerotic lesion size at the aortic valves was stained using Oil Red O and quantified.
Mice treated daily with orally available D-4F demonstrated significant lipid deposit reduction in BrM first after 12 weeks (-16.6%±10.1 compared to baseline group; after 16 weeks -24.0%±10.2; p<0.05). Similarly the size of atherosclerotic lesions at the aortic valves showed also significant reduction after 12 weeks (-24.4%±14.5 compared to baseline group; -19,6% ±12.2 after 16 weeks; p<0.01). There was no significant difference in serum lipid levels among the groups.
Orally available D-4F has a definite systemic effect. It reduces atherosclerotic lesions in the aortic roots as well as BrM lipid depositions. It is known from atherosclerosis research that D-4F acts as a direct lipid acceptor and does not alter serum lipid levels per se. Oral administration seems to be less effective compared to an intravitreal injection of D-4F (2.4 µg; ca. 70% lipid reduction after 30 days, ( Mohi et al., IOVS 2011, 52:ARVO Abstract 5365) and the lipid reduction is delayed (12 weeks). Nevertheless if these compounds prove to slow down AMD progression oral administration would be favourable for patients compared to more invasive intraocular injections.
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