Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration
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-Dawle...
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| Format: | Article |
| Language: | English |
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Elsevier
2013-06-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520357187 |
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| author | Hui Chen Julie-Thu A. Tran Annette Eckerd Tuan-Phat Huynh Michael H. Elliott Richard S. Brush Nawajes A. Mandal |
| author_facet | Hui Chen Julie-Thu A. Tran Annette Eckerd Tuan-Phat Huynh Michael H. Elliott Richard S. Brush Nawajes A. Mandal |
| author_sort | Hui Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T18:52:51Z |
| format | Article |
| id | doaj.art-4e16616f79a74d379f3c7dc3ec829b84 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-21T18:52:51Z |
| publishDate | 2013-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-4e16616f79a74d379f3c7dc3ec829b842022-12-21T18:53:41ZengElsevierJournal of Lipid Research0022-22752013-06-0154616161629Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degenerationHui Chen0Julie-Thu A. Tran1Annette Eckerd2Tuan-Phat Huynh3Michael H. Elliott4Richard S. Brush5Nawajes A. Mandal6Departments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; and; Ophthalmology Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu City, Sichuan, 610072, ChinaDepartments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; andDepartments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; andDepartments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; andDepartments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Departments of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; andDepartments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; andTo whom correspondence should be addressed; Departments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Departments of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; andLight-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.http://www.sciencedirect.com/science/article/pii/S0022227520357187light-induced retinal degenerationphotoreceptorapoptosisfingolimodsphingomyelinase |
| spellingShingle | Hui Chen Julie-Thu A. Tran Annette Eckerd Tuan-Phat Huynh Michael H. Elliott Richard S. Brush Nawajes A. Mandal Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration Journal of Lipid Research light-induced retinal degeneration photoreceptor apoptosis fingolimod sphingomyelinase |
| title | Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration |
| title_full | Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration |
| title_fullStr | Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration |
| title_full_unstemmed | Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration |
| title_short | Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration |
| title_sort | inhibition of de novo ceramide biosynthesis by fty720 protects rat retina from light induced degeneration |
| topic | light-induced retinal degeneration photoreceptor apoptosis fingolimod sphingomyelinase |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520357187 |
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