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

Abstract

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)

Anti-virulence Strategies to Target Bacterial Infections

“…The nanoparticles were able to limit Vero cell cytotoxicity in response to Shiga toxins 1 and 2, but were unable to neutralize certain Shiga toxin 2 variants (Kulkarni et al 2010). Furthermore, C-9, an inhibitor of glycosylceramide synthase, was applied to down-regulate Gb3 expression and prevented the cytotoxic effect of Stx2 on Vero cells (Silberstein et al 2011). Using a rat model of infection, C-9 protected animals against Shiga toxin 2-associated disease and both, prophylactic as well as therapeutic treatment of rats with C-9 decreased expression of Gb3 receptors and the development of a disease phenotype (Kulkarni et al 2010).…”

Alanepe

“…Other promising lines of research are the use of C9, a potent inhibitor of glucosylceramide synthase and GB3 synthesis [8], and the reduction of the level of contamination in the cattle with the use of probiotics [9].…”

Short Review on the Protection by Ouabain of E Coli Toxins

“…Studies trying to obtain this goal have included the development of vaccines or antibodies against the bacteriae or the toxins [2], and the inhibition of the generation of the toxin receptor (globotriosilceramide-GB3) [3,4].…”

“…Changes can be observed in the paper by Amaral et al [13]. 4. In order to determine the possible mechanism of OUA protection, they determined apoptotic activity in both types of cells in the presence of both toxins.…”