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

Abstract

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.

Effect of long‐term stabilization of cationic liposomes as defibrotide delivery system for antithrombotic activity

“…In the present article, cationic liposomes are proposed as possible formulations for intravenous injection of DFT. DFT, a polydeoxyribonucleotide-based drug, was chosen as model compound mimicking the general behavior of nucleic acids because (1) it is a marketed compound with antithrombotic activity [Niada et al, 1982;Girolami et al, 1999;Aydemir et al, 2000]; (2) it has a low molecular weight similar to polymerase chain reaction products and synthetic oligonucleotides [Cimminiello, 1996]; and (3) the in vivo activity of DFT can be easily determined by a hypertension model in rats. Control: rats were given saline (0.9% NaCl) intravenously (1 ml/kg bolus + 2 ml/kg/h infusion) from 60 min before L-NAME treatment until the end of the experiment (30 min after L-NAME treatment).…”

“…The DFT sequence maintains single-stranded polynucleotides with aptameric activity able to bind thrombin or possibly other proteins. DFT possesses a wide pharmacological profile, including profibrinolytic [Pola et al, 1998], antithrombotic-thrombolytic [Uderzo et al, 2000], and antiischemic [Shin et al, 1998], and antiatherosclerotic activity [Aydemir et al, 2000;Jenner et al, 2000]. In addition, DFT is effective in the treatment of peripheral obliterative arterial disease and acute thrombophlebitis [Cimminiello, 1996;Pola et al, 1998].…”

Iron, Atherosclerosis, and Neurodegeneration: A Key Role for Cholesterol in Promoting Iron‐Dependent Oxidative Damage?

“…This possibility, of increased passage of iron into the brain parenchyma in hypercholesterolemia, is consistent with several studies, which showed increased lipid peroxidation in the brain in hypercholesterolemic rabbits. Brain malondialdehyde in rabbits treated with cholesterol was higher than those fed a normal diet 48. Rabbits fed with an atherogenic diet containing 1% cholesterol appeared to show increased lipid peroxidation in tissues including the brain, as measured by thiobarbituric acid reactive substances (TBARS).…”

The protective mechanisms of defibrotide on liver ischaemia–reperfusion injury

“…More recently, studies have raised interest in an 'antiischaemic' action of the DEF, as suggested by its evident protective effect in different models of tissue and organ ischaemia. 2,3 In this experimental study, the effects of DEF on free radical production and consequent alterations in the end-product of in vivo lipid peroxidation and antioxidant enzyme activities were investigated in a rat model of liver I/R injury.…”

“…In the case of severe and prolonged ischaemia, unstable free radical species attack cellular components, causing damage to lipids, proteins and DNA during the early periods of the reperfusion. 2 The survival of the tissue depends on its ability to overcome the toxic effects of oxidants and hence on the capacity of cellular antioxidant systems, which mainly consist of enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), vitamins, including A, E, C and carotene, and some metabolites such as reduced glutathione. 2 Defibrotide (DEF, Crinos Pharmaceuticals, Villa Guardia, Como, Italy) is a polydeoxyribonucleotide extracted from mammalian organs.…”