Background and objectives: To evaluate the effect of a new pyrimidine derivative on the change of mitochondrial function in experimental chronic traumatic encephalopathy. Materials and methods: The study was performed on male mice of the BALB/c line (acute toxicity was assessed) and male rats of the Wistar line, which were modeled chronic traumatic encephalopathy by the method of free fall of the load (weight 150 g from a 50 cm height). The injury to rats was reproduced once a day for 7 days. Further, cognitive functions, changes in sensorimotor deficiency, cerebral blood flow, neuron-specific enolase(NSE), S100β, glial fibrillary acidic protein (GFAP) (in blood serum) and β-amyloid, adenosine triphosphate (ATP) (in brain tissue supernatant) were evaluated. Mitochondrial respiration was also measured. Choline alfoscerate (100 mg/kg) was used as a reference drug. Results: The study found that the use of a new pyrimidine derivative contributed to the preservation of the mitochondrial respirometric function and cognitive functions in rats. In addition, against the administration of test-object marked increase in the concentration of ATP, the velocity of cerebral blood flow was 4.2 times (p < 0.05) and 35.6% (p < 0.05), respectively, as well as reduced concentration and GFAP,NSE, S100β, β-amyloid and sensorimotor deficit at 2.7 (p < 0.05) times; 2 times (p < 0.05); 2.4 times (p < 0.05); of 30.4% (p < 0.05 and 46.5% (p < 0.05), respectively. The LD50 (per os) for the test-object was 4973.56 ± 573.72 mg/kg. Conclusion: Based on the obtained data, high therapeutic efficacy and low systemic toxicity of the application are assumed 4-{2-[2-(3,4-dimethoxyphenyl)-vinyl]-6-ethyl-4-oxo-5-phenyl-4H-pyrimidine-1-Il}benzsulfamide in chronic traumatic encephalopathy.
Introduction: The aim of the study was to evaluate the endothelioprotective activity of 4-hydroxy-3,5-di-tret-butylcinnamic acid in conditions of experimental cerebral ischemia. Materials and Methods: The brain ischemia was reproduced by the method of irreversible right-sided thermocoagulation of the middle cerebral artery. As comparative drugs, mexidol (30 mg/kg) and sulodexide (30 U/kg) were used. The vasodilating function of the vascular endothelium was assessed by the change in the rate of cerebral blood flow when the synthesis of nitric oxide was modified. Antithrombotic function was assessed by changes in the concentration of thromboxane A2, fibrinogen, von Willebrand factor activity and platelet aggregation activity. Serum concentration of C-reactive protein served as a marker of the state of anti-inflammatory endothelial function. To determine the potential mechanism of endothelioprotective activity of 4-4-hydroxy-3,5-di-tret-butylcinnamic acid, the anti-radical activity of this compound toward superoxide and nitrosy-radicals was assessed; and the effect of the compound on the mitochondrial function was studied, by evaluating the functional activity of mitochondrial ATP synthetase and cytochrome-c-oxidase by ELISA. Results and Discussion: In the course of the study, a positive effect of 4-hydroxy-3,5-di-tret-butylcinnamic acid on the state of endothelial function in cerebral ischemia was established, which was expressed in the preservation of vasodilating (restoring the vascular reaction to acetylcholine, nitro-L-arginine methyl ether, L-arginine), antithrombotic (a decrease in the concentration of thromboxane A2, fibrinogen and von Willebrand factor activity by 241.9% (p <0.05), 73.5% (p <0.05), 20.4% (p <0.05), respectively, a decrease in the degree of aggregation and platelet aggregation rate by 56.7 % (p <0.05) and 52.8% (p <0.05), respectively, and anti-inflammatory vascular endothelial function (99.1% C-reactive protein reduction (p <0.05)). The 4-hydroxy-3,5-di-tret-butylcinnamic acid compound in vitro tests suppressed generation of superoxide (IC50 = 1.99 mg/ml) and nitrosyl radical (IC50 = 1.92 mg/ml), eliminated NO-synthase uncoupling, and restored the mitochondrial function (increase in mitochondrial ATP synthase and cytochrome-c-oxidase activity by 23.5% (p <0.05) and 110.8% (p <0.05), respectively). Conclusion: The study demonstrated the presence of endotheliotropic activity of 4-hydroxy-3,5-di-tret-butylcinnamic acid, which is expressed in the preservation of vasodilating, antithrombotic and anti-inflammatory functions of the vascular endothelium in conditions of cerebral ischemia. At the same time, the anti-radical properties of this compound, as well as the direct effect on the functional activity of the NO-synthase system and the improvement of the mitochondrial function, may underlie the endotheliotropic effects of 4-hydroxy-3,5-di-tret-butylcinnamic acid.
1 пятигорский медико-фармацевтический институтфилиал Волгоградского государственного медицинского университета, Россия 2 Северо-Осетинский государственный университет им. Коста Хетагурова, Владикавказ, Россия some asPecTs oF cereBroProTecTiVe acTiViTY oF 4-hYDroXY-3,5-Di-TreTBouTYle oF cinnamic aciD in ischemic Damage oF The Brain in eXPerimenT Voronkov a. V. 1 , abaev V. T. 2 , oganesyan e. T. 1 , Pozdnyakov D. i. 1 1 Pyatigorsk medical and Pharmaceutical institute, a branch Volgograd state medical university, russia 2 north ossetian state university named after costa Khetagurov, Vladikavkaz, russia
Abstract. The Pan-Eurasian Experiment (PEEX) Science Plan, released in 2015, addressed a need for a holistic system understanding and outlined the most urgent research needs for the rapidly changing Arctic-boreal region. Air quality in China, together with the long-range transport of atmospheric pollutants, was also indicated as one of the most crucial topics of the research agenda. These two geographical regions, the northern Eurasian Arctic-boreal region and China, especially the megacities in China, were identified as a “PEEX region”. It is also important to recognize that the PEEX geographical region is an area where science-based policy actions would have significant impacts on the global climate. This paper summarizes results obtained during the last 5 years in the northern Eurasian region, together with recent observations of the air quality in the urban environments in China, in the context of the PEEX programme. The main regions of interest are the Russian Arctic, northern Eurasian boreal forests (Siberia) and peatlands, and the megacities in China. We frame our analysis against research themes introduced in the PEEX Science Plan in 2015. We summarize recent progress towards an enhanced holistic understanding of the land–atmosphere–ocean systems feedbacks. We conclude that although the scientific knowledge in these regions has increased, the new results are in many cases insufficient, and there are still gaps in our understanding of large-scale climate–Earth surface interactions and feedbacks. This arises from limitations in research infrastructures, especially the lack of coordinated, continuous and comprehensive in situ observations of the study region as well as integrative data analyses, hindering a comprehensive system analysis. The fast-changing environment and ecosystem changes driven by climate change, socio-economic activities like the China Silk Road Initiative, and the global trends like urbanization further complicate such analyses. We recognize new topics with an increasing importance in the near future, especially “the enhancing biological sequestration capacity of greenhouse gases into forests and soils to mitigate climate change” and the “socio-economic development to tackle air quality issues”.
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