sphingosine-kinase and Body-Weight

Recent studies have demonstrated that the expression of sphingosine kinase 1, the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1(-/-) mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the sphingosine kinase 1 selective inhibitor, PF-543 and a sphingosine kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodelling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent sphingosine kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodelling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that sphingosine kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for sphingosine kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.

Topics: Animals; Biomarkers; Body Weight; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Female; Heart Ventricles; HEK293 Cells; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Methanol; Mice, Inbred C57BL; Models, Biological; Myocytes, Smooth Muscle; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Pressure; Pulmonary Artery; Pyrrolidines; Signal Transduction; Sulfones; Ventricular Remodeling

Pro-inflammatory cytokines like TNF-α activate sphingosine kinase (SK). Therefore, inhibition of SK is a potential molecular target for the treatment of rheumatoid arthritis.. The primary goal of this study was to assess the efficacy of ABC249640 (a selective SK-2 inhibitor) in two models of rodent arthritis. A secondary goal was to evaluate the pharmacological profile of ABC294640, when given in combination with methotrexate.. The efficacy of ABC294640 was determined by paw diameter/volume measurements, histological evaluations, and micro-CT analyses.. ABC294640 attenuated both collagen-induced arthritis in mice, as well as adjuvant-induced arthritis in rats. With the adjuvant arthritis model, the prophylactic efficacy profile of ABC294640 was similar to indomethacin. Of note, ABC294640 reduced the bone and cartilage degradation, associated with adjuvant-induced arthritis. Rats treated with a suboptimal dose of MTX (50 μg/kg/day) in combination with ABC249640 (100 mg/kg/day) had better anti-arthritis effects in the adjuvant model, than treatment with either agent alone.. Our results suggest that ABC249640 is an orally available drug candidate with a good pre-clinical efficacy profile for the prevention and/or treatment of RA.

Topics: Adamantane; Administration, Oral; Animals; Ankle; Ankle Joint; Arthritis, Experimental; Body Weight; Drug Therapy, Combination; Edema; Enzyme Inhibitors; Female; Foot; Indomethacin; Inflammation; Methotrexate; Mice; Mice, Inbred DBA; Phosphotransferases (Alcohol Group Acceptor); Pyridines; Rats; Rats, Inbred Lew; Splenomegaly; X-Ray Microtomography

Activation of sphingosine kinase (SK) is a key response to many inflammatory processes. The present studies test the hypothesis that an orally available SK inhibitor, ABC294640, would be effective in rodent models of Crohn's disease.. Trinitrobenzene sulfonic acid (TNBS) was administered rectally to mice and rats. Rats were treated with ABC294640 orally alone or in combination with olsalazine and disease progression was monitored.. For both rodent species, treatment with ABC294640 attenuated disease progression. Colon samples from the ABC294640-treated animals had improved histology and cytokine parameters when compared with vehicle-treated animals. The expression of SK was similarly increased in TNBS-treated animals and in human colon tissue specimens from inflammatory bowel disease patients relative to normal, control patients.. Sphingosine kinase may be a critical mediator of colonic damage during intestinal inflammation, and pharmacologic inhibitors of this enzyme may prove useful in the treatment of Crohn's disease.

Topics: Adamantane; Aminosalicylic Acids; Animals; Body Weight; Colon; Crohn Disease; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Epithelial Cells; Female; Gastrointestinal Agents; Humans; Interleukin-1beta; Leukocytes; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Phosphotransferases (Alcohol Group Acceptor); Prednisolone; Pyridines; Rats; Rats, Sprague-Dawley; Treatment Outcome; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The bioactive lipid sphingosine-1-phosphate (S1P) is emerging as an important mediator of immune and inflammatory responses. S1P formation is catalyzed by sphingosine kinase (SK), of which the SK1 isoenzyme is activated by tumor necrosis alpha (TNF-alpha). SK1 has been shown to be required for mediating TNF-alpha inflammatory responses in cells, including induction of cyclooxygenase 2 (COX-2). Because TNF-alpha and COX-2 are increased in patients with inflammatory bowel disease (IBD), we investigated the role of SK1 in a murine model of colitis. SK1(-/-) mice treated with dextran sulfate sodium (DSS) had significantly less blood loss, weight loss, colon shortening, colon histological damage, and splenomegaly than did wild-type (WT) mice. In addition, SK1(-/-) mice had no systemic inflammatory response. Moreover, WT but not SK1(-/-) mice treated with dextran sulfate sodium had significant increases in blood S1P levels, colon SK1 message and activity, and colon neutrophilic infiltrate. Unlike WT mice, SK1(-/-) mice failed to show colonic COX-2 induction despite an exaggerated TNF-alpha response; thus implicating for the first time SK1 in TNF-alpha-mediated COX-2 induction in vivo. Inhibition of SK1 may prove to be a valuable therapeutic target by inhibiting systemic and local inflammation in IBD.

Topics: Animals; Body Weight; Colitis; Colitis, Ulcerative; Colon; Cyclooxygenase 2; Dextran Sulfate; Erythrocytes; Gene Expression Regulation; Humans; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Phosphotransferases (Alcohol Group Acceptor); Sphingosine; Spleen; Tumor Necrosis Factor-alpha