Protection by polaprezinc, an anti-ulcer drug, against indomethacin-induced apoptosis in rat gastric mucosal cells

Polaprezinc [N-(3-aminopropionyl)-L-histidinato zinc] (PZ), an anti-ulcer drug, is a chelate compound consisting of zinc and L-carnosine. PZ has been shown to prevent gastric mucosal injury. In the present study, we investigated the inhibitory effect of PZ on indomethacin (IND)-induced apoptosis in a rat gastric mucosal cell line, RGM1. Pretreatment with PZ suppressed caspase-3 activation and subsequent apoptosis in the cells exposed to 500 mu M IND in a dose-dependent manner, and 50 mu M PZ exhibited the maximum inhibitory effect. Among PZ subcomponents, zinc but not L-carnosine played a pivotal role in this anti-apoptotic function. PZ did not affect mitochondrial cytochrome c release upstream of caspase-3 activation in the IND-induced apoptotic signal pathway. Treatment with 500 mu M IND evidently produced reactive oxygen species (ROS) in RGM1 cells. However, PZ did not scavenge ROS in IND-treated cells. Moreover, N-acetyl-L-cysteine, a potent antioxidant, inhibited ROS generation but did not suppress apoptosis in RGM1 cells exposed to IND. These observations demonstrate a novel pharmacological action of PZ; i.e., that PZ, and in particular its zinc subcomponent, inhibits apoptosis via inhibition of caspase-3 activation but not antioxidant activity.