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Nawajes A Mandal, Megan Stiles, Eleanor Sun, Hui Qi, Jeremy Tan; Systemic administration of FTY720 protects against retinal degeneration in P23H rats by slowing down ceramide synthesis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2480.
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Major retinal degenerative diseases such as Retinis Pigmentosa and age-related retinal degeneration (AMD) involve apoptotic photoreceptor cell death. Ceramide (Cer) is a known sphingolipid metabolite which works as a second messenger in the cell and can induce apoptosis through various mechanisms. Previous studies have linked an increase in ceramide levels with photoreceptor cell death. We hypothesized that inhibiting ceramide synthesis in the cells can protect the retina from photoreceptor degeneration. FTY720 is a known low-toxicity immunomodulator that is the structural analog of sphingosine and can be phosphorylated by sphingosine kinase 2 and can bind to sphingosine-1-phosphate (S1P) receptors acting as an immunosuppressor. FTY720 is also known to block de novo Cer production. In this study we tested the effects of FTY720 systemic dosing in P23H mutant rhodopsin transgenic rats.
P23H mutant rhodopsin transgenic rats possess a single amino acid substitution at codon 23 of the rhodopsin gene which leads to rhodopsin misfolding, ER-stress, and activation of the unfolded protein response eventually leading to rod photoreceptor degeneration. In the P23H-1 model 50% degeneration is noted by 45 days of age as well as a significant increase in cellular Cer at early stages. P23H-1 rats were dosed systemically twice weekly with 2.5mg/kg FTY720 from 15 days of age to 21 days after which the rats were weaned from their mother and the twice weekly dosing was raised to 5mg/kg until 35 days of age. Photoreceptor function by electroretinography (ERG), structural analysis by histology, Cer levels and molecular analysis of the retina were done at P21, P35 and P45. A 12.5% DMSO solution was used as a vehicle control and Sprague Dawley rats were used as a model control.<br />
Preservation of retinal function was measured by ERG analysis. Both scotopic A and B-wave amplitudes were significantly higher in FTY720 treated P23H-1 compared to vehicle treated rats. Histological analysis showed significant preservation of photoreceptors in the inferior retina. A slight preservation of photoreceptors in the superior region was noted as well. FTY720 reduced the level of free Cer in the retina and reduced the expression of inflammatory and apoptotic genes.<br />
We conclude that FTY720 produces a protective effect against retinal degeneration by blocking ceramide production.
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