6-Hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline Demonstrates Neuroprotective Properties in Experimental Parkinson's Disease by Enhancing the Antioxidant System, Normalising Chaperone Activity and Suppressing Apoptosis.

Parkinson's disease (PD) is a neurodegenerative disease, whereby disturbances within the antioxidant defence system, increased aggregation of proteins, and activation of neuronal apoptosis all have a crucial role in the pathogenesis. In this context, exploring the neuroprotective capabilities of compounds that sustain the effectiveness of cellular defence systems in neurodegenerative disorders is worthwhile. During this study, we assessed how 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ), which has antioxidant properties, affects the functioning of the antioxidant system, the activity of NADPH-generating enzymes and chaperones, and the level of apoptotic processes in rats with rotenone-induced PD. Six groups of animals were formed for our experiment, each with 12 animals. These were: a control group, animals with rotenone-induced PD, rats with PD given HTHQ at a dose of 50 mg/kg, rats with PD given HTHQ at a dose of 25 mg/kg, animals with pathology who were administered a comparison drug rasagiline, and control animals who were administered HTHQ at a dose of 50 mg/kg. The study results indicate that administering HTHQ led to a significant decrease in oxidative stress in PD rats. The enhanced redox status in animal tissues was linked with the recovery of antioxidant enzyme activities and NADPH-generating enzyme function, as well as an upsurge in the mRNA expression levels of antioxidant genes and factors Nrf2 and Foxo1. Administering HTHQ to rats with PD normalized the chaperone-like activity and mRNA levels of heat shock protein 70. Rats treated with the compound displayed lower apoptosis intensity when compared to animals with pathology. Therefore, owing to its antioxidant properties, HTHQ demonstrated a beneficial impact on the antioxidant system, resulting in decreased requirements for chaperone activation and the inhibition of apoptosis processes triggered in PD. HTHQ at a dose of 50 mg/kg had a greater impact on the majority of the examined variables compared to rasagiline.

6-Hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline Demonstrates Anti-Inflammatory Properties and Reduces Oxidative Stress in Acetaminophen-Induced Liver Injury in Rats.

We examined the effects of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers of liver injury, oxidative status, and the extent of inflammatory and apoptotic processes in rats with acetaminophen-induced liver damage. The administration of acetaminophen caused the accumulation of 8-hydroxy-2-deoxyguanosine and 8-isoprostane in the liver and serum, as well as an increase in biochemiluminescence indicators. Oxidative stress resulted in the activation of pro-inflammatory cytokine and NF-κB factor mRNA synthesis and increased levels of immunoglobulin G, along with higher activities of caspase-3, caspase-8, and caspase-9. The administration of acetaminophen also resulted in the development of oxidative stress, leading to a decrease in the level of reduced glutathione and an imbalance in the function of antioxidant enzymes. This study discovered that 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline reduced oxidative stress by its antioxidant activity, hence reducing the level of pro-inflammatory cytokine and NF-κB mRNA, as well as decreasing the concentration of immunoglobulin G. These changes resulted in a reduction in the activity of caspase-8 and caspase-9, which are involved in the activation of ligand-induced and mitochondrial pathways of apoptosis and inhibited the effector caspase-3. In addition, 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline promoted the normalization of antioxidant system function in animals treated with acetaminophen. As a result, the compound being tested alleviated inflammation and apoptosis by decreasing oxidative stress, which led to improved liver marker indices and ameliorated histopathological alterations.

6-Hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline Alleviates Oxidative Stress and NF-κB-Mediated Inflammation in Rats with Experimental Parkinson's Disease.

A study was conducted to investigate the effects of different doses of 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ) on motor coordination scores, brain tissue morphology, the expression of tyrosine hydroxylase, the severity of oxidative stress parameters, the levels of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) factor, and the inflammatory response in rats during the development of rotenone-induced Parkinsonism. The findings indicate that HTHQ, with its antioxidant attributes, reduced the levels of 8-isoprostane, lipid oxidation products, and protein oxidation products. The decrease in oxidative stress due to HTHQ led to a reduction in the mRNA content of proinflammatory cytokines and myeloperoxidase activity, accompanying the drop in the expression of the factor NF-κB. These alterations promoted an improvement in motor coordination scores and increased tyrosine hydroxylase levels, whereas histopathological changes in the brain tissue of the experimental animals were attenuated. HTHQ exhibited greater effectiveness than the comparative drug rasagiline based on the majority of variables.

New Hybrid Tetrahydropyrrolo[3,2,1-ij]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation.

Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo[3,2,1-ij]quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa.

Effect of Boron on the Microstructure, Superplastic Behavior, and Mechanical Properties of Ti-4Al-3Mo-1V Alloy.

The decrease of superplastic forming temperature and improvement of post-forming mechanical properties are important issues for titanium-based alloys. Ultrafine-grained and homogeneous microstructure are required to improve both processing and mechanical properties. This study focuses on the influence of 0.01-2 wt.% B (boron) on the microstructure and properties of Ti-4Al-3Mo-1V (wt.%) alloys. The microstructure evolution, superplasticity, and room temperature mechanical properties of boron-free and boron-modified alloys were investigated using light optical microscopy, scanning electron microscopy, electron backscatter diffraction, X-ray diffraction analysis, and uniaxial tensile tests. A trace addition of 0.01 to 0.1 wt.% B significantly refined prior ß-grains and improved superplasticity. Alloys with minor B and B-free alloy exhibited similar superplastic elongations of 400-1000% in a temperature range of 700-875 °C and strain rate sensitivity coefficient m of 0.4-0.5. Along with this, a trace boron addition provided a stable flow and effectively reduced flow stress values, especially at low temperatures, that was explained by the acceleration of the recrystallization and globularization of the microstructure at the initial stage of superplastic deformation. Recrystallization-induced decrease in yield strength from 770 MPa to 680 MPa was observed with an increase in boron content from 0 to 0.1%. Post-forming heat treatment, including quenching and ageing, increased strength characteristics of the alloys with 0.01 and 0.1% boron by 90-140 MPa and insignificantly decreased ductility. Alloys with 1-2% B exhibited an opposite behavior. For the high-boron alloys, the refinement effect of the prior ß-grains was not detected. A high fraction of borides of ~5-11% deteriorated the superplastic properties and drastically decreased ductility at room temperature. The alloy with 2% B demonstrated non-superplastic behavior and low level of strength properties; meanwhile, the alloy with 1% B exhibited superplasticity at 875 °C with elongation of ~500%, post-forming yield strength of 830 MPa, and ultimate tensile strength of 1020 MPa at room temperature. The differences between minor boron and high boron influence on the grain structure and properties were discussed and the mechanisms of the boron influence were suggested.

The new antioxidant 1-benzoyl-6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline has a protective effect against carbon tetrachloride-induced hepatic injury in rats.

Liver diseases with the central pathogenetic mechanism of oxidative stress are one of the main causes of mortality worldwide. Therefore, dihydroquinoline derivatives, which are precursors of hepatoprotectors and have antioxidant activity, are of interest. We have previously found that some compounds in this class have the ability to normalize redox homeostasis under experimental conditions. Here, we initially analyzed the hepatoprotective potential of the dihydroquinoline derivative 1-benzoyl-6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline (BHDQ) for carbon tetrachloride (CCl 4)-induced liver injury in rats. Results suggested that BHDQ normalized the alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase in serum. We also observed an improvement in liver tissue morphology related to BHDQ. Animals with CCl 4-induced liver injuries treated with BHDQ had less oxidative stress compared to animals with CCl 4-induced liver injury. BHDQ promoted activation changes in superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione transferase on control values in animals with CCl 4-induced liver injury. BHDQ also activated gene transcription in Sod1 and Gpx1 via nuclear factor erythroid 2-related factor 2 and forkhead box protein O1 factors. Therefore, the compound of concern has a hepatoprotective effect by inhibiting the development of necrotic processes in the liver tissue, through antioxidation.

New Chemicals Suppressing SARS-CoV-2 Replication in Cell Culture.

Candidates to being inhibitors of the main protease (Mpro) of SARS-CoV-2 were selected from the database of Voronezh State University using molecular modeling. The database contained approximately 19,000 compounds represented by more than 41,000 ligand conformers. These ligands were docked into Mpro using the SOL docking program. For one thousand ligands with best values of the SOL score, the protein-ligand binding enthalpy was calculated by the PM7 quantum-chemical method with the COSMO solvent model. Using the SOL score and the calculated protein-ligand binding enthalpies, eighteen compounds were selected for the experiments. Several of these inhibitors suppressed the replication of the coronavirus in cell culture, and we used the best three among them in the search for chemical analogs. Selection among analogs using the same procedure followed by experiments led to identification of seven inhibitors of the SARS-CoV-2 replication in cell culture with EC50 values at the micromolar level. The identified inhibitors belong to three chemical classes. The three inhibitors, 4,4-dimethyldithioquinoline derivatives, inhibit SARS-CoV-2 replication in Vero E6 cell culture just as effectively as the best published non-covalent inhibitors, and show low cytotoxicity. These results open up a possibility to develop antiviral drugs against the SARS-CoV-2 coronavirus.

Synthesis of 4,5-Dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors.

This study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1H-[1,2]dithiolo[3,4-c]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another heterocyclic fragment. Using the PASS Online software, among the previously synthesized and new derivatives of 1,2-dithiolo[3,4-c]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity. All the synthesized derivatives were screened for their inhibitory assessment against a number of kinases. Compounds which exhibited prominent inhibition percentage in cells (>85%) were also examined for their inhibitory efficiency on human kinases via ELISA utilizing sorafenib as a reference standard to estimate their IC50 values. It was revealed that compounds 2a, 2b, 2c, and 2q displayed a significant inhibition JAK3 (IC50 = 0.36 µM, 0.38 µM, 0.41 µM, and 0.46 µM, respectively); moreover, compounds 2a and 2b displayed excellent activities against NPM1-ALK (IC50 = 0.54 µM, 0.25 µM, respectively), against cRAF[Y340D][Y341D], compound 2c showed excellent activity, and compound 2q showed weak activity (IC50 = 0.78 µM, 5.34 µM, respectively) (sorafenib IC50 = 0.78 µM, 0.43 µM, 1.95 µM, respectively). Thus, new promising preferred structures for the creation of drugs for the treatment of cancer and other multifactorial diseases in the future have been found.

New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling, Synthesis, and Experimental Confirmation.

In the modern world, complications caused by disorders in the blood coagulation system are found in almost all areas of medicine. Thus, the development of new, more advanced drugs that can prevent pathological conditions without disrupting normal hemostasis is an urgent task. The blood coagulation factor XIIa is one of the most promising therapeutic targets for the development of anticoagulants based on its inhibitors. The initial stage of drug development is directly related to computational methods of searching for a lead compound. In this study, docking followed by quantum chemical calculations was used to search for noncovalent low-molecular-weight factor XIIa inhibitors in a focused library of druglike compounds. As a result of the study, four low-molecular-weight compounds were experimentally confirmed as factor XIIa inhibitors. Selectivity testing revealed that two of the identified factor XIIa inhibitors were selective over the coagulation factors Xa and XIa.

The Influence of Signal Polarization on Quantum Bit Error Rate for Subcarrier Wave Quantum Key Distribution Protocol.

In this paper, we consider the influence of a divergence of polarization of a quantum signal transmitted through an optical fiber channel on the quantum bit error rate of the subcarrier wave quantum key distribution protocol. Firstly, we investigate the dependence of the optical power of the signal on the modulation indices' difference after the second phase modulation of the signal. Then we consider the Liouville equation with regard to relaxation in order to develop expressions of the dynamics of the Stokes parameters. As a result, we propose a model that describes quantum bit error rate for the subcarrier wave quantum key distribution depending on the characteristics of the optical fiber. Finally, we propose several methods for minimizing quantum bit error rate.

Accelerated liver recovery after acute CCl4 poisoning in rats treated with sodium phthalhydrazide.

Pharmacotherapy of hepatobiliary disorders is an important issue due to the high prevalence of liver failure, toxic and viral hepatitis and cirrhosis. The number of stimuli that can potentially induce or accelerate liver recovery is limited; in our study we selected sodium phthalhydrazide, which has been found to promote liver regeneration after partial hepatectomy. We examined the effects of phthalhydrazide on liver morphometric, histological and biochemical parameters in rats intoxicated with CCl4. Accelerated liver recovery after CCl4 intoxication in phthalhydrazide-treated animals was evidenced by increased number of liver sinusoidal cells, reduced focal necrosis of hepatocytes and reduced perifocal leukocyte infiltration. Decreased plasma levels of pro-inflammatory cytokines TNF-α and IL-18 and decreased concentrations of IL-6 and IFN-γ in liver homogenates were associated with reduced severity of cholestasis and normalized hepatic protein synthesis in CCl4-intoxicated rats exposed to phthalhydrazide. Anti-inflammatory and immunomodulating properties of phthahlhydrazide can be an important factor contributing to accelerated liver recovery at early stages of acute CCl4-toxic liver impairment.

Appendix A. dithioloquinolinethiones as new potential multitargeted antibacterial and antifungal agents: Synthesis, biological evaluation and molecular docking studies.

Herein we report the design, synthesis, molecular docking study and evaluation of antimicrobial activity of ten new dithioloquinolinethiones. The structures of compounds were confirmed by 1H NMR, 13C NMR and HPLC-HRMS. Before evaluation of their possible antimicrobial activity prediction of toxicity was performed. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. All compounds appeared to be more active than ampicillin and almost all than streptomycin. The best antibacterial activity was observed for compound 8c 4,4,8-trimethyl-5-{[(4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)thio]acetyl}-4,5-dihydro-1H-[1,2]dithiolo[3,4c]quino lone-1-thione). The most sensitive bacterium En.cloacae followed by S. aureus, while L.monocytogenes was the most resistant. All compounds were tested for antifungal activity also against eight fungal species. The best activity was expressed by compound 8d (5-[(4,5-Dihydro-1,3-thiazol-2-ylthio)acetyl]-4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione). The most sensitive fungal was T. viride, while P. verrucosum var. cyclopium was the most resistant one. All compounds were more potent as antifungal agent than reference compound bifonazole and ketoconazole. The docking studies indicated a probable involvement of E. coli DNA GyrB inhibition in the anti-bacterial mechanism, while CYP51ca inhibition is probably responsible for antifungal activity of tested compounds. It is interesting to mention that docking results coincides with experimental.

Two forms of substrate for the bioluminescent reaction in three species of basidiomycetes.

The luminescent response of the enzymatic system of Armillaria borealis on the cold and hot extracts from cell-free culture liquids of Inonotus obliquus, Pholiota sp. and A. borealis was examined. The greatest influence on the light emission produced by the luminescent system of A. borealis was provided by the temperature at which the probes were prepared for assay. Boiling a culture liquid on water bath for a few minutes promoted a multifold increase in the luminescence. The results of luminescence assay suggest that the substance involved in the bioluminescent reaction in higher fungi is presented in culture liquids and mycelia in two forms. In one form, it is ready to interact with the enzymatic system and in the second form, it becomes accessible for the reaction after heat treatment. The pool of thermoactivated substance was found to be much large than the amount of the ready accessible one. We suggest that predecessors of hispidin, which is fungal luciferin precursor, are responsible for this phenomenon. They are not involved in bioluminescence at their original state and are converted into the substrate under the influence of high temperature.

Pathological changes in the cellular structures of retina and choroidea in the early stages of alloxan-induced diabetes.

AIM: To investigate the temporal sequence of pathological changes in the cellular structures of retina and choroidea in the early stages of diabetes in laboratory animals. METHODS: Experimental type 1 diabetes was modeled by three intraperitoneal injections of an alloxan solution into 30 male nonlinear rats at 16 wk of age. The 30th and 60th days from the final alloxan injection were chosen as the endpoints. Light and electron microscopy and morphometric and immunohistochemical studies were performed on histological slices of eyeballs from experimental animals. RESULTS: Diabetic disturbances progressed to 60 d of the experiment. Thus, in the retina, a partial destruction of photoreceptors accompanied by interstitial edema was observed. The morphometric analysis revealed a reduction in the thickness of the retina. A reduction in the number of blood vessels of the choroid with disturbances of the endothelial cells and the vascular walls and a persistent reduction in the number of melanocytes were observed. The number of proliferating Ki-67 positive cells decreased, and the number of macrophages increased with diabetes development. CONCLUSION: The starting point in the development of destructive changes involves early reduction in the number of melanocytes of the choroidea and alterations in the retinal pigment epithelium.

Effects of 1,3,4-thiadiazine compound with antidepressant properties in ligation model of acute pancreatitis.

Based on hypotheses concerning the role of stress in acute pancreatitis development, the experimental approach for the decrease stress damage via the use the compound with proven antistress/neuroleptic action was conducted. The study was aimed to discover 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrobromide (compound L-17) therapeutic action in experimental acute pancreatitis. The experimental model used was the ligation model. The trial was carried out on 50 male Wistar rats with average body weight 180-240 g. Histological picture of the pancreas was studied and biochemical and enzyme-immunoassays were carried out on the first and seventh days. The significant reduction in mortality on the background of L-17 compound administration was observed. While levels of all cytokines increased in induced experimental acute pancreatitis groups, the cytokine level rise was decreased when compound L-17 was administered. On the cellular level, the study revealed L-17's ability to prevent granulocytosis and decrease granulocytes infiltration to inflammatory foci. The decrease in inflammatory reaction magnitude and prevention of abscess formation in experimental acute pancreatitis accompanied by sistemic inflamamtion was due to L-17's ability to reduce neutrophilia and neutrophil entry into the injury zone.

Structural damage to periodontal tissues at varying rate of anesthetic injection.

BACKGROUND: Incorrect administration of an anesthetic during local anesthesia is one of the most important causes of pain symptoms in patients scheduled for dental procedures. The current study assessed the severity of damage to periodontal tissue following different rates of anesthetic administration. METHODS: The research was conducted on 50 outbred male rats with a body mass of 180-240 g. The anesthetic used was 1% articaine. RESULTS: The results showed that administration of the anesthetic at a rapid pace caused structural damage to the periodontal tissue. Further, signs of impaired microcirculation were noted at all rates of administration. Biochemical studies demonstrated changes in the level of glucose and enzymes with the rapid introduction of the anesthetic, indicating severe systemic stress response of the body. CONCLUSIONS: Injection of local anesthetic at any rate of introduction induces vascular congestion in the microcirculatory bloodstream and exudative reactions. Rapid introduction of an anesthetic causes progression of structural changes in the gingival tissue.

Partial recovery from alloxan-induced diabetes by sodium phthalhydrazide in rats.

In the commonly used experimental model of diabetes, a cytotoxic glucose analogue alloxan can selectively destruct pancreatic ß-cells, with characteristics similar to the type-1 diabetes (T1D) in humans. Treatment of diabetic rats with sodium phthalhydrazide partially reversed diabetogenic pathology in the alloxan-induced diabetes. The alloxan-treated rats with permanent hyperglycemia, which further received i.p. twenty daily doses 2mg/kg b.w. phthalhydrazide, showed at 60days of the experiment a significant amelioration of the diabetes status. Hyperglycemia was decreased by 52%, glycated haemoglobin HbA1c returned to control value, insulin concentration significantly increased from 45,4% (alloxan group) to 59,5% (alloxan+phthalhydrazide) of the control values. Importantly, phthalhydrazide treatment of alloxan-treated diabetic rats markedly decreased the concentrationof interleukin-6 (IL-6) and corticosterone level. Morphometric analysis revealed a marked increase in the number of pancreatic islets/mm2, and a number of cells/mm2 in the pancreatic islets. These changes, including 3-fold increase in the number of insulin-producing cells and 2-fold decrease in blood glucose levels, correlated with the increased proliferative activity of pancreatic ß-cells in the diabetic phthalhydrazide-treated animals. Interestingly, the number of CD68+ cells/macrophages in the pancreatic islets, which was relatively high in the alloxan group (63,9+- 16.4/mm2), markedly decreased after the phthalhydrazide treatment (23,6+-7,2/mm2). Taking together with the previous data on the phthalhydrazide-related macrophage silencing, restriction of macrophage quantity in the alloxan-affected pancreatic islets can be possibly one of important events leading to the partial recovery from the ß-cell disruption.

Application of Molecular Modeling to Development of New Factor Xa Inhibitors.

In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs. After validation of molecular modeling methods on well-known factor Xa inhibitors the virtual screening of NCI Diversity and Voronezh State University databases of ready-made low molecular weight species has been carried out. Seventeen compounds selected on the basis of modeling results have been tested experimentally in vitro. It has been found that 12 of them showed activity against factor Xa (IC50 = 1.8-40 µM). Based on analysis of the results, the new original compound was synthesized and experimentally verified. It shows activity against factor Xa with IC50 value of 0.7 µM.

The Chemical Basis of Fungal Bioluminescence.

Many species of fungi naturally produce light, a phenomenon known as bioluminescence, however, the fungal substrates used in the chemical reactions that produce light have not been reported. We identified the fungal compound luciferin 3-hydroxyhispidin, which is biosynthesized by oxidation of the precursor hispidin, a known fungal and plant secondary metabolite. The fungal luciferin does not share structural similarity with the other eight known luciferins. Furthermore, it was shown that 3-hydroxyhispidin leads to bioluminescence in extracts from four diverse genera of luminous fungi, thus suggesting a common biochemical mechanism for fungal bioluminescence.

Effect of a new class of compounds of the group of substituted 5R1, 6H2-1,3,4-thiadiazine-2-amines on the inflammatory and cytokine response in experimental myocardial infarction.

This study investigated the effects of the L-17 compound of the group of substituted 5R1, 6H2- 1,3,4-thiadiazine-2-amines on the immune response and the plasma level of circulating cytokines in acute myocardial infarction (MI) in rats. The study was based upon experimental work which demonstrated the role of local and systemic inflammatory reactions in MI. Acute MI in rats was induced by left coronary artery coagulation. Histological study of the myocardium sections has been carried out at the 1(th) and 7(th) days of the experimental myocardial infarction. Serum activity of creatine phosphokinase (CPK), aspartate aminotransferase (AST), isoenzymes 1 and 2 and lactate dehydroge nase (LDH1-2) were investigated at days 1(st)and 7(th). ELISA analysis for plasma cytokine levels was performed using commercially available test kits following the manufacturer's instructions. Biochemical analysis in animals with the administration of the L-17 compound after MI showed that the AST and CPK levels at days 5 and 7 of experiments did not differ significantly from the values of intact animals. In animals of the group with MI without the administration of the L-17 compound, the IL-1 level 8 times and the TNF level 7.8 times exceeded the normal indicators, while the use of L-17 compound in the therapy resulted in only 1.8 times increase of IL-1 level and 4.7 times increase of TNF level in comparison with the norm. Thus, the introduction of L-17 compound in case of experimental MI delays exudative/alternative phase of inflammation, accelerates granulocytic and decreased the inflammation and anti-inflammation interleukins level.