Improvement of liver function after cold ischemia by melatonin.

Reactive oxygen species (ROS) are considered main effectors of ischemia-reperfusion (I/R) injury in liver transplantation. Melatonin is a potent anti-oxidant also able to regulate electron transport and ATP synthesis by mitochondria that proved to prevent injury to organs subjected to warm I/R. Earlier we demonstrated that livers cold-preserved with either University of Wisconsin or Celsior solutions and reperfused in presence of melatonin produced significantly more bile and had higher ATP levels respect to indole-free reperfusion; no significant effect was noticed on oxidative stress nor on damage to endothelial cells. We hypothesized that the improvement of functionality reflected enhanced performance of hepatocyte mitochondria. We hence searched for in situ evidence to support this assumption, by demonstrating ROS with the DAB-Mn2+-Co2+ histochemical reaction. In control liver staining was very intense in a wide periportal area, decaying towards the centrolobular region; it was strong in a few sinusoidal cells. After cold preservation and reperfusion without melatonin the livers were edematous (mainly for Celsior solution) and staining occurred only in a narrow area of periportal hepatocytes, suggesting poor metabolic activity; sinusoidal cells were mostly unstained. When reperfusion was made in presence of melatonin, the morphology was markedly improved and the ROS reaction, though less intense than in the controls, resumed the trend towards the lobular zonation for both preservation solutions. In conclusion, we demonstrated that melatonin decreased edema, preserved liver morphology and that in this experimental model the ROS in hepatocytes are indicators of mitochondria efficiency rather than injury indexes. These histochemical data confirm that the indole mitigates I/R injury and support melatonin potential in liver transplantation.