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Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720
can delay retinal degeneration
#MMPMID26947037
Stiles M
; Qi H
; Sun E
; Tan J
; Porter H
; Allegood J
; Chalfant CE
; Yasumura D
; Matthes MT
; LaVail MM
; Mandal NA
J Lipid Res
2016[May]; 57
(5
): 818-31
PMID26947037
show ga
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.
|Animals
[MESH]
|Biosynthetic Pathways
[MESH]
|Disease Progression
[MESH]
|Drug Evaluation, Preclinical
[MESH]
|Fingolimod Hydrochloride/*pharmacology/therapeutic use
[MESH]
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