Development of small-molecule inhibitors of sphingosine-1-phosphate signaling

Edmonds, Yvette; Milstien, Sheldon; Spiegel, Sarah

doi:10.1016/j.pharmthera.2011.08.004

Cited by 60 publications

(44 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FTY720 is an analog of sphingosine (Sph) and can be phosphorylated to FTY720-P in vivo by sphingosine kinase (SPHK) 2 to mimic the action of sphingosine 1-phosphate (S1P) (11)(12)(13)(14). The signaling sphingolipids such as Cer, ceramide-1-phosphate (C1P), Sph, and S1P act as important mediators of cell function and are fundamentally involved in many cellular processes (15)(16)(17)(18)(19).…”

Section: Sphingolipid Analysismentioning

confidence: 99%

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

View full text Add to dashboard Cite

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

show abstract

Section: Sphingolipid Analysismentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Systemic FTY720 is phosphorylated to FTY720-P, and as a mimic of S1P, FTY720-P modulates S1P receptor signaling in lymphocyte homing and traffi cking. Treatment with FTY720 causes lymphopenia by signifi cantly reducing the number of circulating lymphocytes, which accumulate in the lymph nodes ( 61,64,65 ). We tested whether suppression of the immune system in the rat may be responsible for protection of retina from light-induced damage by measuring the number of circulating lymphocytes in the peripheral blood after by administering FTY720 before light stress effectively blocked ceramide increase and preserved retinal structure and function.…”

Section: Effect Of Fty720 On Circulating Lymphocytesmentioning

confidence: 99%

Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration

Chen

Tran

Eckerd

et al. 2013

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org pigmentosa and age-related macular degeneration ( 1-3 ). Very few effective therapies exist for this heterogeneous group of diseases because of the complex pathophysiology associated with genetic and environmental factors. Researchers are looking for cellular second messengers involved in the process of cell death which can be targeted for therapies. The sphingolipid metabolite ceramide is a deadly second messenger in the cell and can induce apoptosis through various mechanisms ( 4 ). Recently, increases in ceramide levels have been shown to be associated with photoreceptor and retinal pigment epithelium (RPE) cell death ( 5-8 ). Here we investigated whether ceramide is involved in photoreceptor cell death in light-induced retinal degeneration (LIRD).LIRD is a useful model for studying the mechanism of photoreceptor cell death because intense light exposure induces oxidative stress-mediated apoptosis of photoreceptor cells and causes retinal degeneration ( 3, 9 ). Since its development in 1966 by Noell et al. ( 10 ), this model, in combination with genetic knock-out models (1)(2)(3)(11)(12)(13)(14), has been extensively used to discover many fundamental mechanisms of photoreceptor function and to test various neuroprotective compounds ( 15-21 ).However, the precise mechanism of light-induced retinal degeneration is currently unclear ( 3, 13 ). In past decades, accumulating evidence suggested that ceramide, the core lipid of sphingolipid metabolism, is a key factor in apoptotic cell death ( 4,(22)(23)(24)(25). Various external stressors, such as hypoxia, chemotherapeutic agents, heat, ultravioAbstract 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 ag...

show abstract

“…2 ). This mechanism causes peripheral lymphopenia by 'trapping' effector lymphocytes with lymph nodes [36,37] . Fingolomod (Gylenia, Novartis, Basel), an oral S1P1 agonist, which is currently approved by the US FDA for the treatment of MS, has demonstrated an acceptable safety profile in a large number of patients.…”

Section: Sphingosine-1-phosphate Receptors Antagonists (S1p1-5)mentioning

confidence: 99%

Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place?

Khanna

Mosli²,

Feagan³

2016

Dig Dis

View full text Add to dashboard Cite

Background: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. Key Messages: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the α4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the α4β7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. Conclusions: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve.

show abstract

Development of small-molecule inhibitors of sphingosine-1-phosphate signaling

Cited by 60 publications

References 55 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 de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration

Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place?

Contact Info

Product

Resources

About