1-benzoyl-6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline exerts a neuroprotective effect and normalises redox homeostasis in a rat model of cerebral ischemia/reperfusion.

Ischemia is one of the main etiological factors of stroke and is associated with the development of energy deficiency, oxidative stress, and inflammation. An abrupt restoration of blood flow, called reperfusion, can worsen the effects of ischemia. In our study, we assessed the neuroprotective potential of 1-benzoyl-6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline (BHDQ) in cerebral ischemia/reperfusion (CIR) in rats. Wistar rats, divided into 4 groups were used in the study: sham-operated animals; animals with CIR caused by occlusion of the common carotid arteries and subsequent removal of the occlusions; rats treated with BHDQ at a dose of 50 mg/kg in the presence of pathology; sham-operated animals treated with BHDQ. The analysis of the state of energy metabolism in the brain, the level of the S100B protein and the histological assessment of the brain tissue were carried out. The antioxidant potential of BHDQ was assessed by measuring biochemiluminescence parameters, analysing the level of 8-isoprostane, products of lipid and protein oxidation, concentration of α-tocopherol and citrate, and aconitate hydratase activity during CIR in rats. A study of the effect of BHDQ on the regulation of the enzymatic antioxidant system and the inflammatory processes was performed. We demonstrated that BHDQ has a neuroprotective effect in CIR, reducing histopathological changes in the brain, normalizing pyruvate and lactate concentrations, and the transcripts level of Hif-1α gene. The positive effect of BHDQ was probably due to its antioxidant and anti-inflammatory activity, manifested in a decrease in the parameters of the oxidative stress, decreased mRNA of proinflammatory cytokines and NF-κB factor genes. In addition, BHDQ reduced the load on antioxidant protection enzymes, contributing to a change in their activities, decreased the level of antioxidant gene transcripts and expression of Nrf2 and Foxo1 factors toward control. Thus, BHDQ exhibited a neuroprotective effect due to a decrease in the level of oxidative stress and inflammation and the normalization of redox homeostasis on CIR in rats.

Neuroprotective effect of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline mediated via regulation of antioxidant system and inhibition of inflammation and apoptosis in a rat model of cerebral ischemia/reperfusion.

The aim of the study was the assessment of the neuroprotective potential of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline (DHQ) and its effect on inflammation, apoptosis, and transcriptional regulation of the antioxidant system in cerebral ischemia/reperfusion (CIR) in rats. The CIR rat model was constructed using the bilateral common carotid artery occlusion followed by reoxygenation. DHQ was administered at a dose of 50 mg/kg for three days. Histological staining was performed using hematoxylin and eosin. The level of S100B protein, 8-hydroxy-2-deoxyguanosine, and 8-isoprostane was assessed using an enzyme immunoassay. The intensity of apoptosis was assessed based on the activity of caspases and DNA fragmentation. The activity of enzymes was measured spectrophotometrically, the level of gene transcripts was assessed by real-time PCR. DHQ reduced the histopathological changes and normalized levels of S100B, lactate, pyruvate, and HIF-1 mRNA in the CIR rat model. In addition, DHQ decreased the oxidative stress markers in animals with a pathology. The tested compound also inhibited inflammation by decreasing the activity of myeloperoxidase, expression of interleukins and Nfkb2. DHQ-treated rats with CIR showed decreased caspase activity, DNA fragmentation, and AIF expression. DHQ changed activity of antioxidant enzymes to the control values, decreased the expression of Cat, Gsr, and Nfe2l2, which was overexpressed in CIR, and activated the expression of Sod1, Gpx1, Gsta2, and Foxo1. DHQ showed a neuroprotective effect on CIR in rats. The neuroprotective effect involve mechanisms such as the inhibition of oxidative stress, leading to a reduction in the inflammatory response and apoptosis and the modulation of the antioxidant defense components.

Activity of Antioxidant Defense Enzymes in Rats with Experimental Allergic Encephalomyelitis.

We studied activities of antioxidant system enzymes in tissues of rats with experimental allergic encephalomyelitis. It was shown that the development of pathology is accompanied by deformation of the neurons and axonal degeneration, intensification of free radical oxidation, exhaustion of the reduced glutathione pool, and multidirectional changes in activities of antioxidant enzymes in rat tissues. The observed imbalance in the antioxidant defense system can be associated with excessive glutathione utilization in the glutathione transferase reaction and different severity of the pathological process in the brain and spinal cord. The received data necessitate the search for compounds that can prevent inhibition of antioxidant system components in order to analyze the possibility of their use in the treatment of multiple sclerosis.

[Effect of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on the intensity of free radical processes and the activity of oxidative metabolism enzymes under toxic liver injury in rats]. / Vozdeistvie 6-gidroksi-2,2,4-trimetil-1,2-digidro-khinolina na intensivnost' svobodnoradikal'nykh protsessov i aktivnost' fermentov okislitel'nogo metabolizma pri toksicheskom porazhenii pecheni u krys.

The effect of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers of hepatocytes cytolysis (aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase), parameters reflecting the state of oxidative status (intensity of biochemical luminescence and the content of diene conjugates), and the activity of oxidative metabolism enzymes (aconitate hydratase, glucose-6-phosphate dehydrogenase, NADP-isocitrate dehydrogenase) was studied in rats with CCl4-induced liver injury. The results obtained in the course of the work demonstrated the ability of the test compound to reduce the severity of oxidative stress and liver cells damage, as well as to change the activity of aconitate hydratase and NADP-generating enzymes in the direction of control values. 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline was more effective in normalizing CCl4-induced changes of the analyzed parameters that Carsil used as a reference compound. The tendency to normalize the state of oxidative status and enzyme activity of oxidative metabolism can attributed to hepatoprotective and antioxidant properties of the tested compound.

Effect of 4-Methyl-Phenyl Biguanide on Free Radical Homeostasis and Activity of Oxidative Metabolism Enzymes in Rats with Cardiovascular Pathology Developing against the Background of Rheumatoid Arthritis.

We studied the effect of 4-methyl-phenyl biguanide, a substance chosen by PASS software (Prediction of Activity Spectra for Substance), on oxidative status and activity of oxidation metabolism enzymes participating in limitation free radical processes (aconitate hydratase, glucose-6-phosphate dehydrogenase, and NADP-isocitrate dehydrogenase) in the heart and blood serum of rats with cardiovascular pathology developing against the background of experimental rheumatoid arthritis. Activity of cardiomyocyte cytolysis markers in rat blood serum was also measured. Normalization of the studied parameters under the influence of the test compound in animals with experimental pathology attests to its positive effects on metabolic and free radical processes.

[The effect of biguanide derivatives on oxidative stress in rats with hyperglycemia]. / Vozdeistvie biguanidinovykh proizvodnykh na razvitie oksidativnogo stressa pri giperglikemii u krys.

The effect of the synthetic biguanide derivatives N-[imino(1-piperidinyl)methyl]guanidine (NIPMG) and 1,3-dimethyl-5-[(carbamimidamidomethanimidoil) amino]benzoyl-1,3dicarboxylate (DCB) on the degree of proteins oxidative modification (POM) and the DNA fragmentation, the content of the lipid peroxidation primary products - conjugated dienes (CD), and the activity of glutathione antioxidant system in the liver and heart of rats with experimental hyperglycemia was investigated. Administration of the biguanides (15.0 mg/kg) to hypoglycemic rats promoted reduction of the free radical processes intensity in the studied tissues. Data about CD and POM level changes in hyperglycemic rats treated by NIPMG and DKB correlate with the results of DNA fragmentation degree evaluation. At the same time, the activity of antioxidant enzymes (glutathione peroxidase and glutathione reductase), and the reduced glutathione content in the liver and heart of rats changed toward control values. For metformin, which was used as a comparison drug, changes in the studied parameters in the same direction were also found. These results indicate the ability of the tested biguanide derivatives to exhibit a positive regulatory effect on free radical homeostasis, reducing the degree of oxidative stress at this pathology.

[The effect of the biologically active additive epiphamine on antioxidant and NADPH-generating enzymes activity under experimental cerebral ischemia/reperfusion in rats]. / Vozdeistvie BAD épifamin na aktivnost' antioksidantnykh i NADPH-generiruiushchikh fermentov pri éksperimental'noi ishemii/reperfuzii golovnogo mozga u krys.

The effect of biologically active additive with immunomodulator properties epiphamine on the activity of antioxidant (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase) and NADPH-generating (glucose-6-phosphate dehydrogenase, NADP-isocitrate dehydrogenase) enzymes has been investigated at experimental cerebral ischemia/reperfusion in rats. The results obtained indicate epiphamine-induced changes of these enzymes activities towards control values. Changes in the content of lactate, a marker of the pathology development, have also been found in experimental animals under ischemia and epiphamine administration caused changes similar to those observed in the case of enzyme activities studied. In most cases, the changes were dose-dependent. Thus, epiphamine can be of considerable interest from the point of view of metabolic changes pharmacological correction at the development of the pathology accompanied by oxidative stress.

[The effect of melaxen administration on the tissue oxidative status in rats with brain ischemia/reperfusion]. / Oksidativnyi status tkanei krys pri vvedenii melaksena na fone razvitiia ishemii/reperfuzii golovnogo mozga.

Melaxen administration to rats with brain ischemia/reperfusion was accompanied by a decrease of the lactate level (an organ ischemia marker), biochemiluminescence parameters characterizing the intensity of free radical processes and total antioxidant activity, the content of lipid peroxidation products, activity of superoxide dismutase and catalase, as compared with the values determined in rats with induced brain ischemia/reperfusion. Activity of aconitate hydratase, a sensitive target of free radicals action, and the citrate level in the brain and blood serum of melaxen-treated animals changed towards control values of intact animals. It is assumed that the effect of melaxen is associated with implementation of the antioxidant and protective properties of melatonin, the melaxen constituent, under conditions of post-ischemic reperfusion injury, accompanied by oxidative stress development.

Effects of N-[Imino(1-Piperidinyl)Methyl] Guanidine on the Intensity of Free Radical Processes, Aconitase Activity, and Citrate Level in the Tissues of Rats with Experimental Type 2 Diabetes Mellitus.

Effects of a synthetic biguanide derivative N-[imino(1-piperidinyl)methyl] guanidine (NIPMG) on free radical homeostasis, aconitase activity, and citrate concentration were studied in the liver and blood serum of rats with type 2 diabetes mellitus. Analysis of biochemiluminescence parameters showed that administration of this agent (10 mg/kg body weight) to animals with diabetes reduced the intensity of free radical processes in study tissues relative to the increased values in untreated diabetic animals. Under these conditions, aconitase activity, a principal target of ROS effects, and citrate level in the liver and blood serum of rats approached the control levels. The results show that NIPMG can positively regulate free radical homeostasis and reduce the intensity of oxidative stress in type 2 diabetes mellitus, which was accompanied by normalization of the studied parameters.

[GLUTATHIONE SYSTEM ACTIVITY IN RAT TISSUES UNDER PHENYLETHYL BIGUANIDE ACTION ON THE BACKGROUND OF EXPERIMENTAL BRAIN ISCHEMIA/REPERFUSION DEVELOPMENT].

It was studied the total antioxidant activity, content of primary lipid peroxidation (LPO) products and reduced glutathione, and the activity of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and NADP-isocitrate dehydrogenase in rat tissues under phenylethyl biguanide (phenfor- min) action on the background of experimental brain ischemia/reperfusion development. It is stablished the analyzed parameters, increasing under ischemia/reperfusion conditions in the brain and blood serum of animals, exhibit a decrease upon the introduction of this biguanide derivative. The obtained data can be explained by a decrease in degree of mobilization of the antioxidant system--in particular, of its glutathione chain--in the pathologic state. Hence, there is a need in NADPH supply for the system functioning compared with the pathology. Thus, phenylethyl biguanide demonstrates its antioxidant and protective properties under oxidative stress development that is accompanied by accumulation of the products of free radical oxidation of biomolecules during the ischemic brain injury.

[EFFECT OF MELATONIN ON THE GLUTATHIONE ANTIOXIDANT SYSTEM ACTIVITY IN RAT TISSUES UNDER CONDITIONS OF EXPERIMENTAL RHEUMATOID ARTHRITIS.]

The influence of melatonin on the reduced glutathione content, activity of glutathione peroxidase, glutathione reductase, and glutathione transferase in blood serum, heart, liver, and skeletal muscle of rats under conditions of experimental rheumatoid arthritis development has been estimated. A change in these parameters toward normal control values under the action of hormone has been revealed. The results can be related to realization of the melatonin antioxidant and protective properties under conditions of oxidative stress accompanying the development of rheumatoid arthritis.

[The effect of 3,5-dicarbomethoxyphenylbiguanide on the activity of antioxidant enzymes].

The effect of 3,5-dicarbomethoxyphenylbiguanide, which was selected with the Prediction of Activity Spectra of Substances (PASS) computer program, on the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione transferase in the heart and the blood serum of rats with experimental rheumatoid arthritis was investigated. The studied parameters changed towards control values when the tested compound was injected in animals with the pathology. These results can be explained by the cardioprotective and antioxidant activity of the compound. The data obtained during the study may be used for the development of new preventive and therapeutic agents for the treatment of the rheumatoid arthritis.

Influence of 10-(6'-Plastoquinonyl)decyltriphenylphosphonium (SkQ1) on Oxidative Status in Rats with Protamine Sulfate-Induced Hyperglycemia.

An influence of 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) on oxidative status and activity of some antioxidant enzymes in the liver and blood serum from rats was examined during experimental hyperglycemia developed after injecting protamine sulfate. It was found that SkQ1 lowered glycemic level in rats treated with protamine sulfate. Moreover, it was also accompanied by restoration of the normal range of biochemiluminescence parameters indicating the rate of ongoing free radical processes, magnitude of primary products of lipid peroxidation such as diene conjugates, activity of aconitate hydratase, and level of citrate in rat liver and blood. Hence, it was demonstrated that activity of superoxide dismutase and catalase, increasing during hyperglycemia, was decreased after administering SkQ1. This might be related to the ability of SkQ1 to normalize free-radical homeostasis imbalanced during hyperglycemia.

Effect of SkQ1 on Activity of the Glutathione System and NADPH-Generating Enzymes in an Experimental Model of Hyperglycemia.

We studied the effect of mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) on the antioxidant activity of the glutathione system and NADPH-generating enzymes in liver and blood serum of rats with hyperglycemia induced by protamine sulfate. It was found that intraperitoneal injection of SkQ1 prevented both decrease in reduced glutathione level and increase in activity of glutathione system enzymes--glutathione peroxidase, glutathione reductase, and glutathione transferase. Activity of NADPH-generating enzymes--glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase--was also attenuated by SkQ1. Probably, in this model of hyperglycemia, decreased level of reactive oxygen species in mitochondria led to the decreased burden on the glutathione antioxidant system and NADPH-generating enzymes. Thus, SkQ1 appears to be a promising compound for the treatment and/or prevention of the adverse effects of hyperglycemia.

Activity of Glutathione Antioxidant System and NADPH-Generating Enzymes in Rats with Experimental Rheumatoid Arthritis.

Induction of rheumatoid arthritis in rats was accompanied by an increase in diene conjugate content and glutathione reductase and glutathione peroxidase activities in muscles and blood serum. These changes can be related to mobilization of the glutathione reductase/glutathione peroxidase system coupled with intensification of free radical oxidation. In addition, activity of glucose-6-phosphodehydrogenase and NADP-dependent isocitrate dehydrogenase increased, which can be related to increased demand of NADPH for the glutathione reductase/glutathione peroxidase system. The content of reduced glutathione in muscles and blood serum decreased, probably, due to its utilization for ROS neutralization. Glutathione transferase activity decreased in rheumatoid arthritis, which can be related to shortness of reduced glutathione developing during oxidative stress. The observed shifts in parameters of free radical homeostasis in rheumatoid arthritis are probably associated with intensification of free radical oxidation.

[Effect of melaxen on free radical processes intensity and some antioxidant enzymes activity in rats liver and blood serum under type 2 diabetes mellitus].

The effect of melaxen on free radical processes and activity of superoxide dismutase and catalase in rats with type 2 diabetes mellitus (T2DM) has been investigated. It was established that melaxen administration to diabetic rats caused a decrease of the intensity of free radical processes as evidenced a decrease of the lipid peroxidation primary products content and biochemiluminescence parameters. The activity of the antioxidant enzymes changed towards normal values. These effects were probably induced by the correction of the melatonin level at the result of the melaxen action.

Effects of a Preparation Containing Pantogam, Succinic Acid, and Chitosan on Activities of the Glutathione System and NADPH-Generating Enzymes in Rat Tissues under Conditions of Cerebral Ischemia/Reperfusion.

Treatment with the complex preparation containing pantogam, succinic acid, and chitosan normalized the concentration of reduced glutathione and activities of glutathione peroxidase, glutathione reductase, and some NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and NADPH-isocitrate dehydrogenase) in animals with experimental hypoxia/reperfusion of the brain. These results can be explained by suppression of free radical oxidation and normalization of the antioxidant system related to the neuroprotective, antihypoxic, and antioxidant properties of these substances, their involvement into the regulation of cell metabolism under pathological conditions accompanied by oxidative stress.

[Effect of melaxen and valdoxan on free radical processes intensity, aconitate hydratase activity and citrate content in rats tissues under hyperthyroidism].

The influence of melaxen and valdoxan on the biochemiluminescence parameters, aconitate hydratase activity and citrate level in rats heart and liver during development of experimental hyperthyroidism has been investigated. Administration of these substances promoted a decrease of biochemiluminescence parameters, which had been increased in tissues of rats in response to the development of oxidative stress under hyperthyroidism. Aconitate hydratase activity and citrate concentration in rats liver and heart, growing at pathological conditions, changed towards control value after administration of the drugs correcting melatonin level. The results indicate the positive effect of valdoxan and melaxen on oxidative status of the organism under the development of experimental hyperthyroidism that is associated with antioxidant action of melatonin.

Activity of the glutathione antioxidant system and NADPH-generating enzymes in blood serum of rats with type 2 diabetes mellitus after administration of melatonin-correcting drugs.

We studied the effects of epifamin and melaxen on serum content of reduced glutathione and activities of glutathione peroxidase, glutathione reductase, and NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase) in rats with type 2 diabetes mellitus. The concentration of reduced glutathione was decreased in rats with this disease (by 1.8 times), but increased after treatment with epifamin and melaxen (by 1.6 and 1.7 times, respectively). Activities of glutathione peroxidase, glutathione reductase, and NADPH-generating enzymes returned to the control level. Correction of melatonin concentration after treatment with the test drugs was probably followed by inhibition of free radical processes. The observed changes were accompanied by normalization of activity of the glutathione antioxidant system and NADPH-generating enzymes required for normal function of this system.

[Effect of succinic acid derivatives and chitosan on the oxidation status of tissues in rats with cerebral ischemia/reperfusion model].

The administration of chitosan succinate and N-succinylchitosan to rats with cerebral ischemia/reperfusion model damage leads to a decrease in the level of lactate (marker of ischemic injury development), parameters of biochemiluminescence (measure of free-radical oxidation intensity), and lipid peroxodation products in animal tissues as compared to untreated (pathologic) control. The obtained results show evidence of the ability of tested drugs to decrease the degree of oxidative stress manifestation under cerebral ischemia/reperfusion conditions, which is related to the positive control effect of chitosan-based drugs on the free-radical homeostasis.