78-dihydroxycoumarin has a dual mechanism of action in hepatic ischemia reperfusion injury

摘要

The present study was designed to investigate the protective effect of 7,8-dihydroxycoumarin on hepatic ischemia/reperfusion (I/R) injury in the rats. The rats were divided in three groups of 10 each; normal control, untreated and the 7,8-dihydroxycoumarin treatment groups. The rats in the treatment group received 7,8-dihydroxycoumarin at doses of 15 mg/kg body weight 1 h prior to ischemia and then daily for 2 days. The animals were sacrificed after 1, 12, 24, 36, and 48 h of reperfusion. The results revealed that 7,8-dihydroxycoumarin protected the liver against I/R injury via inhibition of inflammatory response at the early stage (0-24 h). However, in 7,8-dihydroxycoumarin treatment group autophagy was inhibited resulting in intensified I/R injury following 36 h of reperfusion. 7,8-dihydroxycoumarin treatment caused reduction in the level of serum aminotransferase, liver inflammatory cytokines and showed minor liver histopathologic alterations. However, after 36 h of reperfusion treatment group showed similar I/R injury as that of untreated group. It was observed that 7,8-dihydroxycoumarin enhanced the activation of mitogen-activated protein kinase, decreased nuclear release of high-mobility group box 1 and production of inflammatory cytokines. After 36 h 7,8-dihydroxycoumarin promoted hepatic injury through suppression of autophagy and induction of hepatic apoptosis. Therefore, 7,8-dihydroxycoumarin exhibits inhibitory effect on hepatic ischemia during 0-24 h but causes its promotion after 36 h.