title: Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration.
abstract: 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.
authors.affiliation: Departments 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, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; and.
authors.forename: Julie-Thu A
authors.initials: JA
authors.lastname: Tran
authors.affiliation: Departments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; and.
authors.forename: Annette
authors.initials: A
authors.lastname: Eckerd
authors.affiliation: Departments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; and.
authors.forename: Tuan-Phat
authors.initials: TP
authors.lastname: Huynh
authors.affiliation: 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; and.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Elliott
authors.affiliation: Departments of Ophthalmology and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Dean McGee Eye Institute, Oklahoma City, OK 73104; and.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Brush
authors.affiliation: 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; and. Electronic address: mmandal@ouhsc.edu.
authors.forename: Nawajes A
authors.initials: NA
authors.lastname: Mandal
mesh_terms: D000818:Animals; D002518:Ceramides / Q000096:biosynthesis*; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008027:Light / Q000009:adverse effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002518:Ceramides; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: apoptosis; fingolimod; light-induced retinal degeneration; photoreceptor; sphingomyelinase