The thesis is devoted to solution of the problem of increasing the efficacy of treatment of endothelial dysfunction and neurological complications of diabetes mellitus.
This work represents performed study of endothelioprotective effects of cytokine medications of the interleukin series, namely, the receptor antagonist of interleukin-1 (RAIL-1) and interleukin-2 (IL-2) for experimental substantiation of the possibility of their use as effective neuroprotective agents with endotheliotropic action. Comparative medications were antioxidant drugs Tiocetam (nootropics/antihypoxant), Mexidol (nootropics/membrane stabilizer) and Mildronate (anti-ischemic energy-supplying medication), as well as neuropeptide nootropic Cortexin (with tissue-specific action).
For completeness of representations of metabolic disorders occurring in the brain tissues of animals with experimental hyperglycemia on the model of alloxan-induced experimental diabetes mellitus (AEDM), the dynamics of parameters of the endothelium, the activity of free radical damage (the state of the oxidated protein modification, the nitric oxide system and thiol-disulfide system), changes in the carbohydrate-energy state of the brain cells and the morphofunctional characteristics of the neurons of the sensomotor zone and comparably the influence on these options RAIL-1, IL-2 and the comparator agent.
It has been shown for the first time that RAIL-1 and IL-2 have endothelioprotective effects and prevent the development of endothelial dysfunction on the model of alloxan-induced diabetes mellitus and their advantage over tiocetam, mexidol, mildronate, and cortexin. The active effect on the average diameter, area, nucleus density and concentration of VEGF endothelial cells of the cortex capillaries and brain vessels walls was recognized as RAIL-1, the maximum effect on the content of CRI of endothelial cells in the brain vessels walls was revealed by Roncoleukin.
In the course of our experimental studies, it was found that cerebral ischemia was accompanied by severe violations of energy metabolism in the brain (the imbalance of adenyl nucleotides - a sharp decrease in the concentration of ATP, ADP, and an increase in the content of AMF) and the development of uncompensated acidosis. Positive modulation of carbohydrate-energy metabolism by the investigational medications was confirmed by the normalization of the main and additional parameters of energy supply of cells of brain tissues of rats against the background of experimental DM - led to an increase in the level of ATP and ADF against the background of decreasing the level of AMF and a significant increase in the number of pyruvate and malate against the background of parallel decline of lactic acid concentration. It was proved that the maximum effect was observed in the group RAIL-1, Roncoleukin and Cortexin.
For the first time, a comparative analysis of the activity of Tiocetam, Mildronate, Mexidolid, Cortexin, Roncoleukin, and RAIL-1 found that the maximum blocking of toxic manifestations of nitrosating and oxidative stresses (influence on the activity of iNOS, glutathione reductase and glutathione peroxidase, on the level of neurotoxic NTS and recovered forms of glutathione) was noted in RAIL -1 and Roncoleukin. For the first time, a comparative analysis of experimental therapy of alloxan-induced diabetes mellitus with cytokine medications, antioxidants and neuropeptides has shown that the maximum effect on the hydrocarbon-energy state (for the restoration of the ratio of ATP and AMF, levels of pyruvate, malate, lactate) and the severity of the negative changes in the functional state of the brain cells had the maximum effect in the Roncoleukin group (normalization of the density of neurons) and RAIL-1 (stabilization of the area of neuronal bodies and the activity of the synthesis of RNA in them, decrease in the density of apoptotic and destructively-altered neurons in the brain cells)
Thus, on the basis of experimental studies, the high therapeutic potential of a new approach to neuroprotection in diabetic encephalopathy with the use of targeted medications, the interleukin-1 receptor antagonist (RAIL-1) and interleukin-2 (IL-2), which offers wide opportunities for introduction into the medical practice of the proposed method aimed at interrupting the cytokine-dependent mechanisms of endothelial dysfunction in conditions of cerebral ischemia in diabetes mellitus.
For the first time, it has been proven with the help of system analysis that the endothelioprotective effect of Roncoleukin is related to the influence on the degree of binding of VEGF to the endothelium of brain vessels and the capillary network, the activation of enzymes of TDS (mainly GR) and NO-synthase, which leads to stabilization of the levels of reduced thiols and glutathione against the background of lowering the levels of oxidative intermediates TDS, normalizes the energy-carbohydrate metabolism and processes of apoptosis, blocks th
