Pharmacology of the Sphingosine-1-Phosphate Signalling System

Heringdorf, Dagmar Meyer zu; Ihlefeld, Katja; Pfeilschifter, Josef

doi:10.1007/978-3-7091-1368-4_13

Cited by 17 publications

(17 citation statements)

References 73 publications

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“…The latter are catalyzed by specific kinases to their 1-phosphate analogs. S1P binds to S1P receptors to stimulate the differentiation, migration, and survival of a variety of cell types (25). This process makes it highly unlikely that S1P contributes to the inhibition of osteoblast function that we observe in Mx1-Cre:GD1 mice and GL-1-and LysoGL-1-exposed cultures (4).…”

Section: Discussionmentioning

confidence: 83%

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

Mistry

Sun³

et al. 2014

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

100

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The inherited deficiency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD). A vast majority of patients present with nonneuronopathic, type 1 GD (GD1). GBA deficiency causes the accumulation of two key sphingolipids, glucosylceramide (GL-1) and glucosylsphingosine (LysoGL-1), classically noted within the lysosomes of mononuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 pathophysiology is not known. We recently recapitulated hepatosplenomegaly, cytopenia, hypercytokinemia, and the bone-formation defect of human GD1 through conditional deletion of Gba in Mx1-Cre + :GD1 mice. Here we show that the deletion of Gba2 significantly rescues the GD1 clinical phenotype, despite enhanced elevations in GL-1 and LysoGL-1. Most notably, the reduced bone volume and bone formation rate are normalized. These results suggest that metabolism of GL-1 or LysoGL-1 into downstream bioactive lipids is a major contributor to the bone-formation defect. Direct testing revealed a strong inhibition of osteoblast viability by nanomolar concentrations of sphingosine, but not of ceramide. These findings are consistent with toxicity of high circulating sphingosine levels in GD1 patients, which decline upon enzyme-replacement therapy; serum ceramide levels remain unchanged. Together, complementary results from mice and humans affected with GD1 not only pinpoint sphingosine as being an osteoblast toxin, but also set forth Gba2 as a viable therapeutic target for the development of inhibitors to ameliorate certain disabling consequences of GD1.macrophage | knockout mice | S1P

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Section: Discussionmentioning

confidence: 83%

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

Mistry

Sun³

et al. 2014

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

100

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“…There are no specific inhibitors of S1PP, but there is a commercially available inhibitor of S1PL, THI. LX2931, THI’s relative compound, developed by Lexicon Pharmaceuticals, is in a phase II trial for treatment of rheumatoid arthritis patients and is well tolerated 43 .…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

Moruno-Manchon¹,

Uzor²,

Dabaghian

et al. 2015

Sci Rep

103

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Autophagy is an important homeostatic mechanism that eliminates long-lived proteins, protein aggregates and damaged organelles. Its dysregulation is involved in many neurodegenerative disorders. Autophagy is therefore a promising target for blunting neurodegeneration. We searched for novel autophagic pathways in primary neurons and identified the cytosolic sphingosine-1-phosphate (S1P) pathway as a regulator of neuronal autophagy. S1P, a bioactive lipid generated by sphingosine kinase 1 (SK1) in the cytoplasm, is implicated in cell survival. We found that SK1 enhances flux through autophagy and that S1P-metabolizing enzymes decrease this flux. When autophagy is stimulated, SK1 relocalizes to endosomes/autophagosomes in neurons. Expression of a dominant-negative form of SK1 inhibits autophagosome synthesis. In a neuron model of Huntington’s disease, pharmacologically inhibiting S1P-lyase protected neurons from mutant huntingtin-induced neurotoxicity. These results identify the S1P pathway as a novel regulator of neuronal autophagy and provide a new target for developing therapies for neurodegenerative disorders.

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“…Selective S1P 1 modulators, like ponesimod, reduce peripheral lymphocyte count, and are under investigation for treatment of lymphocyte-mediated autoimmune diseases [14], [15]. In humans, the S1P 1 receptor is also involved in the regulation of heart rate and rhythm [7], [16].…”

Section: Discussionmentioning

confidence: 99%

Desensitization by Progressive Up-Titration Prevents First-Dose Effects on the Heart: Guinea Pig Study with Ponesimod, a Selective S1P1 Receptor Modulator

et al. 2013

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Ponesimod, a selective S1P1 receptor modulator, reduces the blood lymphocyte count in all tested species by preventing egress of T and B cells from thymus and peripheral lymphoid organs. In addition, ponesimod transiently affects heart rate and atrioventricular (AV) conduction in humans, effects not observed in mice, rats, and dogs with selective S1P1 receptor modulators, suggesting that the regulation of heart rate and rhythm is species dependent. In the present study, we used conscious guinea pigs implanted with a telemetry device to investigate the effects of single and multiple oral doses of ponesimod on ECG variables, heart rate, and blood pressure. Oral administration of ponesimod did not affect the sinus rate (P rate) but dose-dependently induced AV block type I to III. A single oral dose of 0.1 mg/kg had no effect on ECG variables, while a dose of 3 mg/kg induced AV block type III in all treated guinea pigs. Repeated oral dosing of 1 or 3 mg/kg ponesimod resulted in rapid desensitization, so that the second dose had no or a clearly reduced effect on ECG variables as compared with the first dose. Resensitization of the S1P1 receptor in the heart was concentration dependent. After desensitization had been induced by the first dose of ponesimod, the cardiac system remained desensitized as long as the plasma concentration was ≥75 ng/ml. By using a progressive up-titration regimen, the first-dose effect of ponesimod on heart rate and AV conduction was significantly reduced due to desensitization of the S1P1 receptor. In summary, conscious guinea pigs implanted with a telemetry device represent a useful model to study first-dose effects of S1P1 receptor modulators on heart rate and rhythm. This knowledge was translated to a dosing regimen of ponesimod to be tested in humans to avoid or significantly reduce the first-dose effects.

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Pharmacology of the Sphingosine-1-Phosphate Signalling System

Cited by 17 publications

References 73 publications

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease

Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy

Desensitization by Progressive Up-Titration Prevents First-Dose Effects on the Heart: Guinea Pig Study with Ponesimod, a Selective S1P1 Receptor Modulator

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