Pharmacological activities of crocin in saffron

The effect of crocin on improving ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks is reported. Based on these results, it became evident that crocin prevents the inhibitory effect of ethanol on long-term potentiation (LTP) in the dentate gyrus in vivo. We confirmed that crocin inhibits tumor necrosis factor (TNF)-α-induced apoptosis of PC-12 cells. PC-12 cells showed a rapid increase in cellular ceramide levels, followed by an increase in the phosphorylation of c-Jun kinase (JNK), leading to apoptosis by serum/glucose deprivation in the medium. The production of ceramide was dependent on the activation of magnesium-dependent neutral sphingomyelinase (N-SMase), but not on de novo synthesis. The oxidative stress also decreased the cellular levels of glutathione (GSH), which is the potent inhibitor of N-SMase. Crocin treatment resulted in the prevention of N-SMase activation, ceramide production and JNK phosphorylation. Exploration of the crocin's preventive mechanism in oxidative stress-induced cell death revealed that the activities of GSH reductase and γ-glutamylcysteinyl synthase (γ-GCS) in the γ-glutamyl cycle affected the stable GSH supply that blocks the activation of N-SMase. These results strongly support the importance of the proposed GSH-dependent inhibitory mechanism in oxidative stress-mediated cell death.