771 The opening of the permeability transition pore is responsible for mitochondrial dysfunction and cell death caused by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)

Abstract

a.u. for control, p<0.01, n=6). However, this increase was abolished in the presence of MPG (96±2 a.u., p<0.01). Co-treatment of ceramide with cyclooxygenase inhibitors, 10μM NS 398 or 1μM nimesulide also abolished the cytoprotection afforded by ceramide (cell viability: NS 398 + Cer 66±2% and nimesulide + Cer 66±1%; p<0.01 vs Cer; n=4) and partially decreased the amount of ROS produced by ceramide. Inhibition of other potential ROS-producing systems with NOS inhibitor (L-NAME, 5mM), xanthine oxidase inhibitor (allopurinol, 0.1mM) or NADPH oxidase inhibitor (Cadmium chloride, 1mM) failed to abolish ceramide cytoprotection. In conclusion, these data strongly suggest that ROS production mediated, in part, by cyclooxygenase would play a major role in the cytoprotective effect of ceramide.