title: Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration.
abstract: Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. With a wide range of mutations and conditions leading to degeneration, targeting downstream processes is necessary for developing effective treatments. Ceramide and sphingosine-1-phosphate, a pair of bioactive sphingolipids, are involved in apoptosis and its prevention, respectively. Apoptotic cell death is a potential driver of RD, and in order to understand the mechanism of degeneration and potential treatments, we studied rhodopsin mutant RD model, P23H-1 rats. Investigating this genetic model of human RD allows us to investigate the association of sphingolipid metabolites with the degeneration of the retina in P23H-1 rats and the effects of a specific modulator of sphingolipid metabolism, FTY720. We found that P23H-1 rat retinas had altered sphingolipid profiles that, when treated with FTY720, were rebalanced closer to normal levels. FTY720-treated rats also showed protection from RD compared with their vehicle-treated littermates. Based on these data, we conclude that sphingolipid dysregulation plays a secondary role in retinal cell death, which may be common to many forms of RDs, and that the U.S. Food and Drug Administration-approved drug FTY720 or related compounds that modulate sphingolipid metabolism could potentially delay the cell death.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Dean McGee Eye Institute, Oklahoma City, OK 73104.
authors.forename: Megan
authors.initials: M
authors.lastname: Stiles
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Dean McGee Eye Institute, Oklahoma City, OK 73104.
authors.forename: Hui
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Dean McGee Eye Institute, Oklahoma City, OK 73104.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Dean McGee Eye Institute, Oklahoma City, OK 73104.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Dean McGee Eye Institute, Oklahoma City, OK 73104.
authors.forename: Hunter
authors.initials: H
authors.lastname: Porter
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allegood
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298 Research and Development, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA 23249 Virginia Commonwealth University School of Medicine, Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298 Virginia Commonwealth University Institute of Molecular Medicine and the Virginia Commonwealth University Johnson Center, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.affiliation: Beckman Vision Center, University of California, San Francisco School of Medicine, San Francisco, CA 94143.
authors.forename: Douglas
authors.initials: D
authors.lastname: Yasumura
authors.affiliation: Beckman Vision Center, University of California, San Francisco School of Medicine, San Francisco, CA 94143.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Matthes
authors.affiliation: Beckman Vision Center, University of California, San Francisco School of Medicine, San Francisco, CA 94143.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: LaVail
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Dean McGee Eye Institute, Oklahoma City, OK 73104 Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 mmandal@ouhsc.edu.
authors.forename: Nawajes A
authors.initials: NA
authors.lastname: Mandal
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D058499:Retinal Dystrophies / Q000188:drug therapy / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D013107:Sphingolipids; D013108:Sphingomyelin Phosphodiesterase; D000068876:Fingolimod Hydrochloride
keywords: FTY720; P23H line 1 rats; apoptosis; ceramide; fingolimod; hexosyl-ceramide; photoreceptors; retina; sphingomyelin; sphingomyelinase