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Md Nawajes Mandal, Hui Chen, Julie-Thu Tran, Michael Elliott, Richard Brush; Ceramide Biosynthesis Inhibition Protects the Retina from Light-Induced Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1963.
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Light-induced retinal degeneration (LIRD) in albino rats causes apoptotic photoreceptor cell death. Ceramide, a sphingolipid metabolite, is a second messenger for apoptosis. We tested whether increases in ceramide mediate photoreceptor apoptosis in light-stressed retinas and if inhibition of ceramide formation can protect the retina from LIRD.
Sprague Dawley (SD) rats were exposed to 2,700 lux white light for 6 h and the retinal levels of ceramide and its intermediary metabolites were measured by GC-MS or ESI-MS/MS. Enzymes of the de novo biosynthetic and sphingomyelinase pathways of ceramide generation were assayed, and gene expression was measured by qRT-PCR. The synthetic drug FTY720, analogous to sphingosine and known to inhibit de novo ceramide biosynthesis, was administered intraperitoneally before light damage. The dosage and temporal effect of FTY720 on the retina in vivo was measured by histological and functional analyses.
Retinal ceramide levels increased concurrently with the increase of dihydroceramide and dihydrosphingosine immediately and at various time points after light stress, well before active apoptosis. Light stress in retina induces ceramide generation predominantly through the de novo pathway. Intraperitoneal (IP) injection of FTY720 (10 mg/kg) prevented ceramide generation by the de novo pathway and protected retinal structure and function. We determined that the neuroprotection of FTY720 was independent of its immunosuppressive action.
We conclude that ceramide increase by de novo biosynthesis mediates photoreceptor apoptosis in the LIRD model and that inhibition of ceramide production protects the retina against light stress.
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