ASMase inhibitors

Notably, in a study on mouse hepatocytes in vitro, D.A. Brenner and Y.Hannun confirmed that activation of ASMase and generation of eeramide (specifically of chain length Cl6) contributes to TNF-a-induced hepatocyte apoptosis (Osawa et al., 2005), but they did not see an involvement of downstream GD3 formation in their model. Another observation to be mentioned in this context is that TNF-a-induced apoptosis in the human myelogenous leukemia cells was blocked by the ASMase inhibitor SR33557 (Higuchi et al.,... 

ASMase-deficient mice are protected in models of lethal endotoxic shock induced by LPS alone (Haimovitz-Friedman et ah, 1997) or LPS after galacto-samine pre-treatment (Garcia-Ruiz et ah, 2003). Also, treatment of mice with the ASMase inhibitor NB6 enhances survival in endotoxemia (Claus et ah,... 

Currently known non-natural ASMase inhibitors (see Fig. 19.3 for selected structures) may be classified as follows (i) compounds that block AMSase activity by direct interaction with the enzyme (ii) compounds that block ASMase activity in cells in an indirect way. The first class is the most interesting from the pharmaceutical point of view, but only few examples of such ASMase... 

J.Norris and collaborators showed that also acid ceramidase activity in cells vanishes following treatment with desipramine (Elojeimy et ah, 2006) thus, the compound depletes lysosomes of both a ceramide generating and consuming enzyme (and few authors have studies the net effect on cellular ceramide levels when using such inhibitors). Therefore, the many studies in the literature using this class of ASMase inhibitors have to be taken with caution firm conclusions can only be reached when effects seen with these compounds are backed up by experiments with genetically ASMase deficient cells or cells depleted for ASMase by using siRNA. 

While ASMase-deficient mice survive lethal doses of LPS (see above), the serum levels of TNF-a-induced by sublethal doses of LPS are similar to those in WT mice (Haimovitz-Friedman et ak, 1997) isolated ASMase-deficient macrophages respond to LPS with a normal pattern of cytokine secretion (Manthey and Schuchman, 1998). Thus, there is no evidence that ASMase is important for LPS-induced inflammatory responses. A recent report showed that imipramine, an inhibitor of cellular ASMase activity, blocked LPS-induced TNF-a secretion from differentiated human monocyte-like THP-1 cells (Cuschieri et ak, 2007). However, in our hands imipramine has no effect on cytokine secretion from these cells or from monocytes isolated from human blood (A.Billich, unpublished observations). 

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