Magdalena Izdebska

Estimation of oxidative stress parameters in rats after simultaneous administration of rosuvastatin with antidepressants.

BACKGROUND Patients commonly receive statin drugs for the primary or secondary prevention of cardiovascular events and also commonly receive antidepressant drugs for the treatment of depression. A many-year polypharmacotherapy can lead to increased side effects of these drugs. It may lead to an oxidation-reduction imbalance and the growth of a generation of reactive oxygen species (ROS) which may induce cellular dysfunctions. METHODS The aim of this study was to assess oxidative stress parameters in the blood of rats after simultaneous administration of rosuvastatin (10mg/kg) with paroxetine (10mg/kg) or citalopram (10mg/kg). The activity of glutathione peroxidase (GPX) was determined in whole blood, and the activity of glutathione reductase (GR) and the total antioxidant status (TAS) were determined in the serum. RESULTS The 14-day simultaneous administration of rosuvastatin with paroxetine or citalopram caused an increase in glutathione peroxidase and glutathione reductase activity and did not influence the level of the total antioxidant status. Rosuvastatin (10mg/kg) or citalopram (10mg/kg) administered alone to rats for 14 days did not affect the examined parameters. The 14-day application of paroxetine (10mg/kg) significantly decreased a glutathione peroxidase activity, increased a glutathione reductase activity and did not affect the level of TAS. CONCLUSIONS The observed changes may indicate an increased activity of the enzyme system preventing oxidation, which appears to be the effect of the reaction on the severity of oxidative stress during the combined treatment with rosuvastatin and antidepressants.

8-Cyclopentyl-1,3-dimethylxanthine enhances effectiveness of antidepressant in behavioral tests and modulates redox balance in the cerebral cortex of mice

The objective of our study was to investigate whether 8-cyclopentyl-1,3-dimethylxanthine (CPT), associated with the adenosine system, enhances the antidepressant efficacy of antidepressant. All experiments were carried out on Albino Swiss mice. Following drugs: CPT (3 mg/kg) and imipramine (15 mg/kg) were administered intraperitoneally (ip), 60 min before tests. Two behavioral tests on antidepressant capability – a forced swim test (FST) and a tail suspension test (TST) – were performed. To examine whether co-administration of CPT with antidepressants affects the redox balance, the lipid peroxidation products (LPO), glutathione (GSH), glutathione disulfide (GSSG), nicotinamide adenine dinucleotide phosphate (NADP+), and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were determined in the cerebral cortex. The results have demonstrated a CPT-induced enhancement of the antidepressant-like effect of imipramine both in the FST and TST, which may indicate that the adenosine system may be involved in the increasing the effect of antidepressant. Co-administration of CPT with imipramine, such as imipramine alone, decreased the NADP+ and LPO concentrations and increased the GSH/GSSG ratio in comparison to the control, which may confirm beneficial – but comparable to imipramine – effect on redox balance under environmental stress conditions. An increase in the concentration of GSSG in the cortex of animals treated with imipramine in ineffective dose compared to control and no such changes after combined administration of both drugs may suggest a favorable oxidation-reduction potential resulting from their synergistic antidepressant effect.

Chronic Variable Stress Is Responsible for Lipid and DNA Oxidative Disorders and Activation of Oxidative Stress Response Genes in the Brain of Rats

Chronic environmental stress is associated with reactive oxygen species (ROS) overproduction and the pathogenesis of depression. The purpose of this study was to evaluate biochemical and molecular changes associated with ROS generation in the brains of rats submitted to chronic variable stress. Male Wistar rats (50–55 days old, weighing 200–250 g) were divided in two groups (n = 10): control and stressed. Rats in the stressed group were exposed to stress conditions for 40 days. The animals were decapitated and the brain samples were collected. In prefrontal cortex, we measured the following biochemical parameters: lipid peroxidation and concentration of glutathione—GSH, GSSG, GSH/GSSG ratio, glutathione peroxidase, and glutathione reductase activities. In the hippocampus marker of DNA, oxidative damage and expression of DNA-repairing genes (Ogg1, MsrA) and gene-encoding antioxidative transcriptional factor (Nrf2) were determined. The results demonstrate indirect evidence of ROS overproduction and presence of oxidative stress. They also reveal disruption of oxidative defense systems (decreased GR activity, diminished GSH/GSSG ratio, and decreased Nrf2 expression) and activation of the oxidative DNA repair system (increased Ogg1 and MsrA expression). Together, the presented data suggest that independent activation of oxidative stress response genes occurs in chronic variable stress conditions.

The positive synergism of CPT and MK-801 in behavioral tests and in reduction of environmental stress and redox signaling changes in mice cerebral cortex.

BACKGROUND Depressive disorders are associated with oxidative stress. Therefore, it is interesting if antidepressants can affect redox equilibrium and signaling. The first step of our study was to determine the influence of the adenosine system on the antidepressant-like activity of noncompetitive antagonist of the NMDA (N-methyl-d-aspartate) receptor complex - dizocilpine (MK- 801). To this aim, two behavioral tests commonly used to assess the antidepressant capability of drugs - the forced swim test (FST) and tail suspension test (TST), were performed. Locomotor activity was estimated to verify and exclude false positive/negative results in the FST and TST. To examine whether antidepressants affect redox equilibrium, we have investigated lipid peroxidation products (LPO), GSH (glutathione), GSSG (glutathione disulfide), NADP+ (nicotinamide adenine dinucleotide phosphate) and NADPH (reduced nicotinamide adenine dinucleotide phosphate) in the cerebral cortex of mice following administration of CPT (8-cyclopentyl-1,3-dimethylxanthine) and MK-801 (dizocilpine) under environmental stress conditions. METHOD The experiments were carried out using male Albino Swiss mice (25-30 g). The drugs were administered ip., alone and simultaneously, 60 min before tests. RESULTS The behavioural tests results showed that CPT (3 mg/kg) potentiated the antidepressant-like activity of MK-801 (0.05 mg/kg) and the observed effects were not due to the increase in mice locomotor activity. Positive synergism of CPT and MK-801 in reduction of environmental stress conditions was revealed. In this group an increase in GSH and GSSG without changes in GSH/GSSG ratio and reduction of LPO was found. The level of lipid peroxidation products was also decreased in group receiving CPT and MK-801 separately. CONCLUSION Examined antidepressant agents may increase antioxidant defences however further studies are needed with different range of time.

New hydrazide-hydrazones and 1,3-thiazolidin-4-ones with 3-hydroxy-2-naphthoic moiety: Synthesis, in vitro and in vivo studies

In this research we synthesized, identified and evaluated new hydrazide-hydrazones (1-3) and 1,3-thiazolidin-4-one derivatives (4-6) for in vitro and in vivo activity. New hydrazide-hydrazones (1-3) were obtained by the condensation reaction of 3-hydroxy-2-naphthoic acid hydrazide with appropriate aldehydes. Synthesized hydrazide-hydrazones (1-3) were subjected to cyclization reaction with mercaptoacetic acid which afforded with new 1,3-thiazolidin-4-one derivatives (4-6). Among 1,3-thiazolidin-4-one derivatives tested (4-6), compound 6 exhibited highest and most selective cytotoxicity towards human renal adenocarcinoma cells (769-P) and it did not affect the growth of normal cells (H9c2, GMK). Whereas its hydrazide-hydrazone (compound 3) showed significant antiproliferative activity against both tested human cancer cell lines: renal adenocarcinoma (769-P) and hepatocellular carcinoma (HepG2), however with less selectivity. The in vivo studies focused on the antinociceptive activity of newly synthesized 1,3-thiazolidin-4-one derivatives (4-6). The preliminary screening of novel compounds showed that 1,3-thiazolidin-4-one derivatives (4-6) are safe and not toxic against CNS of mice. Among tested derivatives one compound (6) displayed significant analgesic activity.

The beneficial effects of resveratrol on steatosis and mitochondrial oxidative stress in HepG2 cells

Nonalcoholic fatty liver disease (NAFLD) is currently one of the most common chronic liver diseases, especially in developed countries. One group of substances with a potential use in the treatment of NAFLD are plant polyphenols, represented by resveratrol. The aim of this study was to evaluate the effect of resveratrol on steatosis and oxidative stress in HepG2 cells. The steatosis of cells was carried out using free fatty acids: oleic or palmitic acid and their mixtures. Steatosis was visualized using the intracellular lipid staining by Nile Red dye with a fluorescence microscope. This study also determined the viability of cells and mitochondrial membrane potential. The current study showed that fatty acids and their mixtures induced fat overloading in HepG2 cells. In the group of cells incubated with oleic acid (OA), observed changes were moderate with prevailing micro-vesicular steatosis. In case of cells incubated with palmitic acid (PA) and the mixtures of fatty acids, micro- and macro-vacuolar steatosis occurred in most of the cells. Resveratrol decreased steatosis in HepG2 cells induced by OA, PA, as well as their mixtures, and in most of experimental groups did not reduce cells viability. Resveratrol reduced the oxidative stress in HepG2 cells treated with fatty acids mixtures.

Preliminary Pharmacological Screening of Some Thiosemicarbazide, s-triazole, and Thiadiazole Derivatives

Two thiosemicarbazide derivatives 1 and 2, three 2-amino-1,3,4-thiadiazole derivatives 3-5, and three N1- substituted-4-methyl-1,2,4-triazole-5-thione derivatives 6-8 were synthesized and evaluated for their central nervous system effects using rodent behavioral models. With the exception of 6, all compounds were devoid of neurotoxicity and they did not affect the body temperature of mice. New lead structures 1-4 with potential analgesic activity were identified.

Cytotoxic Effect of Combined Treatment with Ukrain and Methotrexate on Kidney Cells of Green Monkey

Abstract In in vitro study on green monkey kidney (GMK) cell culture, the cytotoxicity of Ukrain, methotrexate (MTX), and their combination was investigated. The effect of these drugs and their combination on viability (MTT test) and apoptosis of the cells was assessed. The IC10 and IC50 values for Ukrain and MTX were also indicated. After 24 h of incubation of GMK cells with Ukrain, IC10 amounted to 84.6 μmol/L and IC50 was 256.3 μmol/L, while MTX IC10 amounted to 7.18 μmol/L and IC50 was 154.8 μmol/l. After 24 h of simultaneous incubation of GMK cells with 50 μmol/L of Ukrain and 5.5 μmol/L of MTX, 15.33 % of cytotoxicity of the drugs in LDH test was found. The most significant increase in the cytotoxicity (42.10 %) was noted after 24 h incubation of GMK cells with 150 μmol/L of Ukrain and 5.5 μmol/L of MTX. Likewise, in the MTT assay the greatest decrease in the cells viability was found after incubation with 150 μmol/L of Ukrain and 5.5 μmol/L of MTX. The evaluation of apoptosis also indicated the adverse effect of combined application of both drugs on GMK cells.