Inhibition of rat cerebral mitochondrial respiration by cyclosporins A, D, and G and restoration with trimetazidine.

Abstract

The aim of this work was to investigate possible inhibitory effects of Ca+ and different cyclosporins (Cs) on the rat brain mitochondrial respiratory control ratio (RCR) and whether or not these effects could be antagonized by trimetazidine (TMZ). The RCR was evaluated as the state 3/state 4 ratio of oxidative phosphorylation. CsA, D, and G inhibited about 10% of RCR in a concentration-dependent manner with EC50 of 57, 19 and 7 nM, respectively, whereas CsH did not modify RCR. TMZ was able to fully antagonize this inhibitory effect in a concentration-dependent manner with EC50 of 5,200, 180, and 1 nM, respectively. The Ca2+ added to the mitochondrial preparation decreased RCR in a concentration-dependent manner with a maximal effect of 46% obtained with 100 microM Ca2+. In the presence of TMZ (100 microM), the inhibitory effect of Ca2+ was partly reversed (9%). TMZ alone showed no inhibitory or stimulant effect on RCR. These results show that restoration of RCR by TMZ is due to a Ca(2+)-dependent mechanism, promoting Ca2+ efflux from the mitochondrial matrix. However, Ca2+ efflux is only partial in case of Ca2+ overload. These data suggest that TMZ may restore ATP synthesis in circumstances where neither Ca2+ overload, nor a prooxidant have generated a RCR decrease.