Ceramide production associated with retinal apoptosis after retinal detachment

Ranty, Marie–Laure; Carpentier, Stéphane; Cournot, Maxime; Rico‐Lattes, Isabelle; Malecaze, F; Levade, Thierry; Delisle, Marie–Bernadette; Quintyn, J.–C.

doi:10.1007/s00417-008-0957-6

Cited by 30 publications

(26 citation statements)

References 43 publications

(58 reference statements)

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“…The processes of apoptotic cell death is integral to major retinal diseases including RP, Stargardt's disease, Leber's congenital amaurosis, and AMD (38)(39)(40)(41). Recent evidence suggests a strong correlation between Cer signaling and survival and homeostasis of photoreceptor and RPE cells (8,(42)(43)(44)(45)(46)(47)(48). In this study, we found significant alterations in the sphingolipid profile in P23H-1 rat retina at early age points (P22) when their photoreceptors begin to degenerate.…”

Section: Discussionsupporting

confidence: 48%

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

Stiles

Sun

et al. 2016

Journal of Lipid Research

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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 vehicletreated 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

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Section: Discussionsupporting

confidence: 48%

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

Stiles

Sun

et al. 2016

Journal of Lipid Research

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“…Similarly, in the murine 661W photoreceptor cell line, oxidative stress stimulated acid sphingomyelinase and increased ceramide levels, thereby activating the mitochondrial apoptotic pathway and the caspase cascade (19). Finally, in a rabbit model of retinal apoptosis, ceramide increased after experimental retinal detachment (20). Altogether, these studies document that the accumulation of ceramide is associated with retinal degeneration and suggest that pharmacological interventions altering sphingolipid metabolism may have therapeutic potential.…”

mentioning

confidence: 77%

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

Strettoi

Gargini

Novelli

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Retinitis pigmentosa (RP) is a genetic disease causing progressive apoptotic death of photoreceptors and, ultimately, incurable blindness. Using the retinal degeneration 10 (rd10) mouse model of RP, we investigated the role of ceramide, a proapoptotic sphingolipid, in retinal degeneration. We also tested the possibility that photoreceptor loss can be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. Retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Single intraocular injections of myriocin, a powerful inhibitor of serine palmitoyl-CoA transferase, the ratelimiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Short-term noninvasive treatment lowered retinal ceramide in a manner similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting transcorneal drug administration. Prolonged treatment (10-20 d) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Transcorneal administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies.sphingolipid | apoptosis | electroretinography | morphology

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“…Pretreatment with S1P protects photoreceptors from retinal detachment-induced apoptosis ( 185 ). Recent work from our laboratory shows that S1P prevents photoreceptor death during development in culture [( 188 ); Figs.…”

Section: Sphingosine In the Retinamentioning

confidence: 99%

Regulating survival and development in the retina: key roles for simple sphingolipids

Rotstein

Miranda

Abrahan

et al. 2010

Journal of Lipid Research

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tions as structural membrane components and energetic fuels. However, the fi ndings of the previous half century have extended these roles, shedding light on their indisputable relevance as signaling molecules controlling key aspects of cellular life and development. The identifi cation of diacylglycerol and inositol 1,4,5 triphosphate ( 1 ) as second messengers seemed at the time a peculiarity of these lipids. The subsequent fi ndings of the roles of arachidonic acid metabolites ( 2 ), platelet activating factor ( 3 ), and other minor inositol lipids ( 4 ) in cell signaling began to establish that being intracellular messengers was not an oddity but a habitual task for lipids in cells. The family of lipid signaling molecules largely expanded in the last two decades, when several sphingolipids were successively shown to regulate a multiplicity of cell functions. Sphingosine (Sph) was the fi rst sphingolipid to be established as a bioactive lipid, involved in the regulation of protein kinase (PK)C activity ( 5 ). Ceramide (Cer) and sphingosine-1-phosphate (S1P) were next shown to signal a myriad of cell functions and the number of sphingolipid molecules with bioactive properties has gone on enlarging in recent years ( 6, 7 ).Though a vast literature exists on the functions of sphingolipids in several tissues, less is known concerning its roles in the eye, and in the retina in particular. Accumulation of sphingolipids originated in defects in the lysosomal Abstract Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems. This review summarizes the roles of these simple sphingolipids in different tissues and then analyzes their possible functions in the retina. Alterations in proliferation, neovascularization, differentiation, and cell death are critical in major retina diseases and collective evidence points to a role for sphingolipids in these processes. Cer induces infl ammation and apoptosis in endothelial and retinal pigmented epithelium cells, leading to several retinopathies. S1P can prevent this death but also promotes cell proliferation that might lead to neovascularization and fibrosis. Recent data support Cer and Sph as crucial mediators in the induction of photoreceptor apoptosis in diverse models of oxidative damage and neurodegeneration, and suggest that regulating their metabolism can prevent this death. New evidence proposes a central role for S1P controlling photoreceptor survival and differentiation. Finally, this review discusses the ability of trophic factors to regulate sphingolipid metabolism and transactivate S1P signaling pathways to control survival and development in retina photoreceptors. When asked about the roles of cellular lipids, the fi rst thought usually coming to our minds re...

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Ceramide production associated with retinal apoptosis after retinal detachment

Abstract: Retinal apoptosis during experimental retinal detachment is associated with in vivo production of ceramide.

Cited by 30 publications

References 43 publications

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

Regulating survival and development in the retina: key roles for simple sphingolipids

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