Effect of a new De-N-acetyl-lysoglycosphingolipid on chemically-induced inflammatory bowel disease: possible mechanism of action

Abstract

A new, orally active de-N-acetylated lysoglycosphingolipid (WILD20) was evaluated as antiinflammatory agent using a model of chemically-induced inflammatory bowel disease (IBD) in the rat to mimic human ulcerative colitis and Chron's disease. IBD was induced by hapten trinitrobenzenesulphonic acid (TNB). WILD20, orally administered as preventive or curative, was demonstrated to be efficacious at daily dosages of 0.1-1 mg/kg for 4-5 days. Damage scores, body weight, spleen weight, colonic tissular levels of LTB4, myeloperoxidase (MPO) and malondialdehyde (MDA) are influenced and brought into parameters of normality. Histological observation demonstrated quicker healing, better repair, reduced inflammation, and poor eosinophil degranulation. The mechanisms underlying WILD20 antiinflammatory effects were investigated: whereas WILD20 fails to show a direct effect on PKC, it reduces PKC translocation to the membrane; cellular PLA2 was consequently greatly reduced through this mechanism and thought to be responsible for WILD20 efficacy towards chemically-induced IBD.

In vitro andin vivo impact of a new glycosphingolipid on neutrophils

“…WILD20 was recently found to inhibit PKC translocation in intact cells [3]; down regulation of neutrophil PKC is known to reduce oxidations [12]. In order to verify this point neutrophils were incubated with WILD20 using two different stimuli.…”

“…WILD20 a new lysoglycosphingolipid obtained through alkaline hydrolysis of GM1, was proved to block PLA2 through inhibition of PKC translocation [3]. This produced antiplatelet effects [-2] as well as anti-inflammatory effects, in a model of chemically induced bowel disease.…”

“…Encouraging results were obtained in inflammatory bowel disease, where the substance influenced leukocyte chemotaxis, especially chemotaxis of eosinophils and neutrophils at inflammation sites [3].…”

Phospholipase A2 inhibitors in development

“…Wild-20 (de-N-acetyl-lyso-glycosphingolipid-derivative; Glaxo Wellcome) was detected as an orally active anti-inflammatory agent using a model of chemicallyinduced rat inflammatory bowel disease [143]. WILD-20 was effective after either preventive or therapeutic administration of rather low doses (0.1 -1 mg/kg for four to five days).…”

“…WILD-20 was effective after either preventive or therapeutic administration of rather low doses (0.1 -1 mg/kg for four to five days). Histological observation demonstrated quicker and better wound repair, reduced inflammation, diminished cell accumulation or degranulation of cells, and decreased LTB4 levels in the colonic tissue [143]. Although Wild-20 failed directly to inhibit PKC, it reduced PKC translocation to the membrane, and as a consequence cPLA2 activity was greatly diminished since cPLA2 has to be phosphorylated and translocated to the membrane [19,96].…”