Neutral sphingomyelinases mediate the release of ceramide from sphingomyelin in cellular membranes and can be activated by certain stresses. Ceramide can act as a signaling molecule in its own right, or it can be further processed to generate sphingosine (and sphingosine-1-phosphate). GW 4869 is a cell-permeable, non-competitive inhibitor of neutral sphingomyelinases (IC50 = 1 μM), but does not affect acid sphingomyelinase activity. It inhibits TNF-α-mediated sphingomyelin hydrolysis (100% inhibition at 20 μM) and TNF-α-induced cell death in MCF-7 cells without interfering with activation of NF-κB or glutathione depletion in response to TNF. GW 4869 also reduces the inhibitory effect of oxidized phospholipid products on lipopolysaccharides-mediated induction of interleukin-8 in human aortic endothelial cells and prevents hypoxia-induced pulmonary vasoconstriction in rats in vivo.
