Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration
Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration
复制标题
FTY720 抑制从头神经酰胺生物合成可保护大鼠视网膜免受光诱导变性
DOI：
10.1194/jlr.m035048
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发表时间：
2013-06-01
影响因子：
6.5
通讯作者：
Mandal, Nawajes A.
中科院分区：
文献类型：
--
作者：
Chen, Hui;Tran, Julie-Thu A.;Mandal, Nawajes A.
白化病大鼠的光诱导视网膜变性（LIRD）导致感光细胞凋亡。神经酰胺是细胞凋亡的第二信使。我们测试了神经酰胺的增加是否介导LIRD中的感光细胞凋亡，以及神经酰胺合成的抑制是否保护视网膜。将Sprague-Dawley大鼠暴露于2，700 lux白色光6 h，并通过GC-MS或电喷雾电离串联质谱法测量神经酰胺及其中间代谢物的视网膜水平。测定神经酰胺生成的从头生物合成和鞘磷脂酶途径的酶，并测量基因表达。通过组织学和功能分析测定神经酰胺合成酶抑制剂FTY 720对LIRD视网膜的剂量和时间效应。视网膜神经酰胺水平的增加与增加的二氢神经酰胺在光应激后的各个时间点一致。视网膜中的光应激主要通过从头途径诱导神经酰胺产生，这通过全身施用FTY 720（10 mg/kg）来防止，从而保护视网膜结构和功能。FTY 720的神经保护作用与其免疫抑制作用无关。我们的结论是，在LIRD模型中，通过从头生物合成增加神经酰胺介导了感光细胞凋亡，并且抑制神经酰胺的产生可以保护视网膜免受光应激。
Light-induced retinal degeneration (LIRD) in albino rats causes apoptotic photoreceptor cell death. Ceramide is a second messenger for apoptosis. We tested whether increases in ceramide mediate photoreceptor apoptosis in LIRD and if inhibition of ceramide synthesis protects the retina. Sprague-Dawley 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 electrospray ionization tandem mass spectrometry. Enzymes of the de novo biosynthetic and sphingomyelinase pathways of ceramide generation were assayed, and gene expression was measured. The dosage and temporal effect of the ceramide synthase inhibitor FTY720 on the LIRD retina were measured by histological and functional analyses. Retinal ceramide levels increased coincident with the increase of dihydroceramide at various time points after light stress. Light stress in retina induces ceramide generation predominantly through the de novo pathway, which was prevented by systemic administration of FTY720 (10 mg/kg) leading to the protection of retinal structure and function. 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.