Inhibition of glycolipid biosynthesis by N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin protects against the inflammatory response in hapten-induced colitis

Shen, Chong; Bullens, Dominique; Kasran, Ahmad; Maerten, Philippe; Boon, Louis; Aerts, Johannes M. F. G.; Assche, Gert Van; Geboes, Karel; Rutgeerts, Paul; Ceuppens, Jan L.

doi:10.1016/j.intimp.2004.04.008

Cited by 40 publications

(48 citation statements)

References 26 publications

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“…AMP-DNM has been shown to convey a potent antiinflammatory effect in animal models of inflammatory bowel disease induced by chronic macrophage activation, 14 and our group also reported a beneficial effect of AMP-DNM in mouse models of the metabolic syndrome, a disease characterized by chronic low-grade inflammation. 15,32 In the APOE*3 Leiden mice studied here, AMP-DNM treatment also decreased tumor necrosis factor-␣ and monocyte-chemoattactant protein-1 (MCP-1/CCL2) expression (Supplemental Figure II), and therefore its antiinflammatory action may have contributed to the strong antiatherogenic effect of AMP-DNM.…”

Section: Discussionmentioning

confidence: 64%

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Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Bietrix

Lombardo

Roomen

et al. 2010

ATVB

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Objective-The iminosugar N-(5Ј-adamantane-1Ј-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase catalyzing glycosphingolipid (GSL) biosynthesis, ameliorates diabetes and reduces liver steatosis in ob/ob mice. Because an accumulation of sphingolipids, including sphingomyelin and GSLs, has been reported in atherosclerotic lesions in animal models and in humans, the objective of this study was to determine whether AMP-DNM also exerts beneficial effects on the development of atherosclerosis. Methods and Results-APOE*3 Leiden mice, maintained on a high-cholesterol diet, were treated for up to 18 weeks with AMP-DNM. The iminosugar prevented hyperlipidemia, generated a less atherogenic lipid profile, and induced a dramatic reduction in the development of atherosclerotic lesions. At the highest dose, no lesions were detectable. The effect of AMP-DNM was associated with a decrease in liver cholesterol, an increase in bile secretion, and enhanced excretion of cholesterol in the feces. Similar effects of AMP-DNM were observed in mice deficient for the low-density lipoprotein receptor. Conclusion-By

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Section: Discussionmentioning

confidence: 64%

“…13 Furthermore, this compound was shown to convey a potent antiinflammatory effect. 14,15 On the basis of all these observations, we postulated that AMP-DNM might also show beneficial effects on cardiovascular disease. Therefore, the aim of this study was to evaluate the effect of AMP-DNM on the progression of atherosclerosis.…”

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confidence: 98%

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Bietrix

Lombardo

Roomen

et al. 2010

ATVB

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“…We have also seen that C-9 prevented the focal loss of goblet cells observed in colon of Stx2 injected rats. It was reported that an inhibitor of intracellular glycolipid biosynthesis decreased goblet cell loss in colon of mice with inflammatory bowel disease, causing antiinflammatory activity (33). In this work, the treatment with C-9 could protect the colonic mucosa against inflammatory responses triggered by sStx2 by decreasing the expression levels of Gb3 in the leukocytes and, in consequence, the inflammation associated to these cells (34,35).…”

Section: Discussionmentioning

confidence: 73%

A Glucosylceramide Synthase Inhibitor Protects Rats Against the Cytotoxic Effects of Shiga Toxin 2

et al. 2011

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Postdiarrhea hemolytic uremic syndrome is the most common cause of acute renal failure in children in Argentina. Renal damage has been strongly associated with Shiga toxin (Stx), which binds to the globotriaosylceramide (Gb3) receptor on the plasma membrane of target cells. The purpose of the study was to evaluate the in vivo effects of C-9, a potent inhibitor of glucosylceramide synthase and Gb3 synthesis, on kidney and colon in an experimental model of hemolytic uremic syndrome in rats. Rats were i.p. injected with supernatant from recombinant Escherichia coli expressing Stx2 (sStx2). A group of these rats were orally treated with C-9 during 6 d, from 2 d prior until 4 d after sStx2 injection. The injection of sStx2 caused renal damage as well as a loss of goblet cells in colonic mucosa. Oral treatment with C-9 significantly decreased rat mortality to 50% and reduced the extension of renal and intestinal injuries in the surviving rats. The C-9 also decreased Gb3 and glucosylceramide expression levels in rat kidneys. It is particularly interesting that an improvement was seen when C-9 was administered 2 d before challenge, which makes it potentially useful for prophylaxis. (Pediatr Res 69: 390-394, 2011)

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“…46 Within the D-gluco series, the N-alkyl derivatives (1 and 5-9) are moderate GCS inhibitors, with octyl and nonyl deoxynojirimycin derivatives 8 and 9 being the most potent. Interestingly, the dialkyl ether-substituted deoxynojirimycin derivatives (16)(17)(18)(19)(20)(21) are in general quite a bit more potent, again with the compounds having the larger substituents being the most potent. The most potent GCS inhibitor from this series, compound 21, emulates leads 3 and 4 in potency.…”

mentioning

confidence: 99%

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

Ghisaidoobe

Bikker

Bruijn

et al. 2010

ACS Med. Chem. Lett.

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Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated L-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.

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Inhibition of glycolipid biosynthesis by N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin protects against the inflammatory response in hapten-induced colitis

Cited by 40 publications

References 26 publications

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

A Glucosylceramide Synthase Inhibitor Protects Rats Against the Cytotoxic Effects of Shiga Toxin 2

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

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