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RA Radu, NL Mata, PA Sieving, GH Travis; Treatment Of Abcr-/- Mice With Isotretinoin Inhibits Accumulation Of Lipofuscin . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4579.
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Purpose: Mutations in the ABCR gene are responsible for recessive Stargardt's macular degeneration (STGD). An important pathological feature of STGD is accumulation of lipofuscin pigment in cells of the RPE. The major fluorophore of lipofuscin is N-retinylidene-N-retinylethanolamine (A2E). Similar to patients with STGD, mice with a knockout mutation in abcr massively accumulate A2E in RPE cells. A2E is formed by sequential condensation of all-trans-retinaldehyde (atRAL) with phosphatidylethanolamine. atRAL is approximately two-fold elevated in abcr-/- retinas following light exposure. In the current study we attempted to inhibit A2E accumulation by treating abcr-/- mice with isotretinoin (Accutane). Isotretinoin is an inhibitor of 11-cis-retinol dehydrogenase, and has been shown to slow rhodopsin regeneration and prevent photolytic damage in rat retinas without causing photoreceptor degeneration. Methods: Isotretinoin was administered daily to abcr-/- mice at 20 mg/kg by i.p. injection for up to two months. We analyzed ocular tissues histologically and biochemically for A2E and its precursor, A2PE-H2. Results: We observed virtually complete inhibition of A2E and A2PE-H2 accumulation in abcr-/- RPE cells during the treatment period compared with untreated and sham-treated abcr-/- controls. Strikingly, A2PE-H2 was virtually eliminated from abcr-/- retinas following one month of treatment with isotretinoin. Conclusion: These data establish that treatment with isotretinoin inhibits accumulation of A2E in abcr-/- RPE. A2E accumulation is a critical early event in the etiology of STGD. Given the strong phenotypic similarities between abcr-/- mice and humans with STGD, these data suggest further that isotretinoin may be useful to slow disease progression in STGD patients.
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