fumaric-acid and Ischemia

While performing surgical treatment of the localized form of renal cell cancer by means of open or laparoscopic partial nephrectomy, renal warm ischemia is an important issue. Using renal warm ischemia allows to prevent parenchymal bleeding, to optimize conditions for resection of the tumor and to increase significantly the efficiency of hemostasis. However, an important problem is the probability of ischemic hypoxic damage of the remaining part of the kidney tissue during renal warm ischemia and renal functional impairment in the postoperative period.. To compare nephroprotective activity of sodium fumarate, mannitol and furosemide using experimental model of 30- and 60-minute renal warm ischemia in rabbits.. The experiments were carried out on 360 conventional male-rabbits of the "Chinchilla" breed weighed 2,6+/-0,3 kg which were allocated into 10 groups. The control group No1 included intact animals, the control group No2 included the rabbits in which renal artery was not clamped. For the animals from the trial groups (No3-No10) the experimental model of 30- and 60-minute renal warm ischemia was used. In groups No3 and No4 no drugs were provided. Other rabbits undergone renal warm ischemia with a protection by sodium fumarate (groups No5 and No6 - 1,5 ml/kg IV), lasix (groups No7 and No8 - 3,0 mg/kg IV) and mannitol (No9 and No10 - 1,0 g/kg IV). The influence of renal warm ischemia on the renal tissue ultrastructure and the levels of NGAL, Cystatin-C and creatinine in blood and urine were studied.. During experimental pharmacologically uncorrected 30-minute renal warm ischemia in animals, edema of the terminal part of microvilli of the proximal tubules epithelium, an increase of lysosome number in the hyaloplasm of epithelial cells, appearance of flaky content of medium electronic density in the lumens of distal tubules and collecting tubules, as well as sharp peak-like increase of NGAL and cystatin-C in blood and urine were observed. Increasing the time of ischemia up to 60 minutes was accompanied by more severe disturbances. In groups where sodium fumarate, lasix and mannitol were used the observed ultrastructural disturbances were expressed to lesser extent, whereas sodium fumarate demonstrated the best nephroprotective activity. After using mannitol the severity of disturbances was less than in the groups where mannitol, lasix or sodium fumarate were not given. Lasix and sodium salt of fumaric acid showed a higher nephroprotective activity. The best results were received in the animals received sodium fumarate.. The studied drugs provided a nephroprotective effect regarding ischemia of rabbit kidney. The effect of sodium fumarate was the most pronounced, followed by furosemide and, to a lesser extent, mannitol. Use of sodium fumarate allows to protect and stimulate the kidney tissue effectively during oxygen deprivation under ischemic state.

Topics: Animals; Female; Fumarates; Furosemide; Humans; Ischemia; Kidney; Kidney Neoplasms; Lipocalin-2; Male; Mannitol; Rabbits; Warm Ischemia

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.

Topics: Adenosine Monophosphate; Animals; Aspartic Acid; Citric Acid Cycle; Disease Models, Animal; Electron Transport; Electron Transport Complex I; Fumarates; Ischemia; Malates; Male; Metabolomics; Mice; Mitochondria; Myocardial Infarction; Myocardium; Myocytes, Cardiac; NAD; Reactive Oxygen Species; Reperfusion Injury; Stroke; Succinate Dehydrogenase; Succinic Acid