The protective mechanisms of defibrotide on liver ischaemia-reperfusion injury.

During some surgical interventions, temporary occlusion of the hepatic blood supply may cause ischaemia-reperfusion (I/R) injury and hepatic dysfunction. In this study the protective effect of defibrotide (DEF) was evaluated in a rat model of liver I/R injury. Four groups of rats were subjected to the following protocols: saline infusion without ischaemia, DEF infusion without ischaemia, DEF infusion with hepatic I/R, and saline infusion with hepatic I/R. After a midline laporatomy, liver ischaemia was induced by 45 min of portal occlusion. DEF 175 mg/kg(-1) was infused before ischaemia in 10 ml of saline. The same volume of saline was infused into the control animals. At the end of the 45-min reperfusion interval, the animals were sacrified. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme activities were determined in haemolysates, and malondialdehyde (MDA) level in the liver tissue was measured. Tissue MDA levels were significantly higher in the I/R plus saline group compared to the sham operation control groups (p < 0.01 and p < 0.05, respectively). Tissue MDA levels decreased in the DEF plus I/R group compared to the I/R plus saline group (p < 0.05), but DEF could not reduce tissue lipid peroxidation to the levels of the control sham operation groups. SOD and GSH-Px enzyme activities were significantly higher in DEF-treated animals than in the other groups (p < 0.05). These results suggest that DEF protects liver against I/R injury by increasing the antioxidant enzyme levels.

Effects of defibrotide on aorta and brain malondialdehyde and antioxidants in cholesterol-induced atherosclerotic rabbits.

The effects of a high-cholesterol diet in the presence and absence of defibrotide, a single-stranded polydeoxyribonucleotide compound, on the lipid peroxidation product malondialdehyde, endogenous antioxidant enzymes catalase, glutathione peroxidase, and the antioxidant thiol compound GSH were investigated. Forty male New Zeland white rabbits were divided into four groups each consisting of 10 rabbits. Group I received a regular rabbit chow diet and group II 1% cholesterol plus regular chow, group III was given defibrotide (60 mg/kg per day p.o. in water) and was fed with regular chow, and group IV received defibrotide plus 1% cholesterol for 9 weeks. Blood cholesterol and malondialdehyde, catalase, glutathione peroxidase, and GSH were determined before starting the experimental diet regimen (basal). After 9 weeks, the same parameters were determined in blood, aorta, and brain tissues (end -experiment). Aortic tissue was examined under a light microscope for morphological alterations indicative of atherosclerosis. The increase in serum total cholesterol was greater in group II than group IV. Plasma malondialdehyde in group II was higher than in group III. Brain malondialdehyde in group II was higher than all other groups, and aortic malondialdehyde in this group was higher than group I and III. Serum catalase activity decreased in group II and increased in group III, compared with basal values. Brain catalase activity in group I was higher than group II, and aorta catalase in group IV was higher than in group I and III. Blood glutathione peroxidase activity in group III and IV was higher than basal. GSH concentrations decreased significantly in the cholesterol-fed groups (group II and IV). Histological alterations in the cholesterol-fed groups were more pronounced in group II. The increased levels of malondialdehyde in plasma, aorta, and brain tissue of group II suggest a role of oxygen free radicals in the pathogenesis of cholesterol-induced atherosclerosis. The higher malondialdehyde values in the brain tissues of animals in group II compared with group IV suggest a protective role of defibrotide in the brain against lipid peroxidation in the oxidant stress of cholesterol-induced atherosclerosis. Increased catalase activities in the blood and aortic tissues and increased glutathione peroxidase activities in the blood of rabbits receiving defibrotide suggest an induction of these antioxidant enzyme activities by defibrotide. These results imply that anti-atherosclerotic, anti-ischemic effects of this drug may be due to the beneficial effects on the oxidant-antioxidant balance of various tissues.