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Journal Article 2014; 35(2): 129-136 PubMed PMID: 24878971 Citation  Keywords:  Animals, Antidepressive Agents:pharmacology, Depressive Disorder:drug therapy, Disease Models, Animal, Drug Evaluation, Preclinical, Helplessness, Learned, Male, Panax:chemistry, Phytotherapy, Plant Extracts:chemistry, Polygala:chemistry, Rats, Rats, Wist.   

OBJECTIVES: The present study aimed to evaluate whether SYG, a Chinese herbal formula, could produce antidepressant-like effects in learned helplessness (LH) model and chronic mild stress (CMS) model in rats. The mechanism underlying the antidepressant-like action was investigated by exploring BDNF signaling way in the hippocampus.

MATERIAL AND METHODS: SYG was administrated for 5 consecutive days (100 and 200 mg/kg/day, intragastrically) in the learned helplessness model; SYG was administered daily by gastric gavages during both the 5-week stress session and behavior tests periods in the chronic mild stress model (100 and 200 mg/kg). The serum corticosterone level was measured in the learned helplessness model. Levels of BDNF and Tyrosine-related kinase B (TrkB), were evaluated in the hippocampus of chronic mild stress model.

RESULTS: A deficit in avoidance learning and higher corticosterone level were observed in learned helplessness rats. SYG significantly reduced this deficit and reversed the corticosterone alteration. CMS induced significant reduction of sucrose intake in the sucrose preference test, an increased latency to feed in the novelty-suppressed feeding test and an increased immobility time in the forced swim test as compared to the control. It was also found that BDNF and TrkB levels were decreased in CMS model. Chronic treatment of SYG significantly suppressed the behavioral changes and up-regulated the BDNF signal pathway in the hippocampus.

CONCLUSION: Our results suggest that SYG alleviates depression induced by LH and CMS model. The antidepressant-like activity of SYG is likely mediated by activation the BDNF signal pathway in the hippocampus....

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Journal Article 2013; 34(Suppl 2): 43-54 PubMed PMID: 24362092 Citation  Keywords:  Animals, Antineoplastic Agents:pharmacokinetics, Benzo(a)pyrene:pharmacology, Biotransformation:drug effects, Cytochrome P-450 CYP1A1:metabolism, Cytochrome P-450 CYP1A2:metabolism, Cytochrome P-450 Enzyme System:metabolism, Drug Evaluation, Preclinical, .   

OBJECTIVES: The aim of this study was to investigate a role of cytochrome P450 (CYP) and peroxidase in ellipticine oxidative activation in two mouse strains differing in expression of NADPH:CYP reductase (POR) [the HRN (Hepatic Cytochrome P450 Reductase Null) mice, in which POR is deleted in hepatocytes and its wild-type (WT) counterpart], and in levels of CYP1A1/2 and cytochrome b5 that were modulated by treatment of these mouse models with a CYP1A inducer, benzo[a]pyrene (BaP).

METHODS: Ellipticine-DNA adducts were detected by 32P-postlabeling. HPLC was employed for the separation and characterization of ellipticine metabolites.

RESULTS: Hepatic microsomes of HRN and WT mice activate ellipticine to form ellipticine-derived DNA adducts. A 2.2- and 10.4-fold increase in amounts of ellipticine-derived DNA adducts formed by liver microsomes was caused by exposure of HRN and WT mice to BaP, respectively. The results found and utilization of NADPH and arachidonic acid, cofactors of CYP- and cyclooxygenase (COX)-dependent enzyme systems, respectively, as well as inhibitors of CYP1A1/2 and 3A, demonstrate that the CYP1A and 3A enzymes play a major role in ellipticine activation in liver microsomes. In addition, the COX enzyme is important in ellipticine activation in liver of HRN mice.

CONCLUSION: The CYP1A and 3A enzymes activate ellipticine mainly in liver of WT mice, whereas peroxidase COX plays this role in liver of HRN mice. Treatment of mice with BaP increases an impact of CYP1A on ellipticine activation. A pattern of expression levels of these enzymes plays a crucial role in their impact on this process....

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Journal Article 2011; 32(Suppl 1): 15-24 PubMed PMID: 22167222 Citation  Keywords:  Alanine Transaminase:blood, Albumins:analysis, Animals, Antioxidants:metabolism, Carps:blood, Ceruloplasmin:metabolism, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Environmental Monitoring, Herbicides:pharmacology, Metabolome, Oxidatio.   

OBJECTIVES: Effects of the herbicide formulation Click 500 SC (terbuthylazine 500 g/l) on common carp Cyprinus carpio were assessed through biometric, biochemical, haematological and antioxidant indices, induction of xenobiotic metabolizing enzymes and histological examination of selected tissues.

DESIGN: The fish were exposed to the formulation with terbuthylazine concentrations of 380 ng/l (environmental concentration); 60 µg/l and 550 µg/l for up to 91 days. Haematological indices were assessed using unified methods of haematological examination in fish. Biochemical indices in plasma were measured by biochemical analyzer, ferric reducing ability of plasma (FRAP) and ceruloplasmin activity were determined spectrophotometrically. Concentration of total cytochrome P450, glutathione-S-transferase activity and glutathione content were assessed spectrophotometrically in liver. Activity of liver ethoxyresorufin-O-deethylase (EROD) activity was measured spectrofluorimetrically. Histopathological examination of liver, skin, gills, spleen, cranial and caudal kidney was performed by light microscopy.

RESULTS: An increase (p<0.05) was observed in hepatosomatic index and condition factor in fish from the environmental concentration. A decrease (p<0.05) in haemoglobin and mean corpuscular haemoglobin concentration (MCHC) was found in fish treated with terbuthylazine of 550 µg/l. There was a decline in mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) (p<0.05) in terbuthylazine of 60 µg/l and 550 µg/l. Triglycerides (TAG) (p<0.01) were elevated in all pesticide-treated groups. Alanine aminotransferase (ALT) (p<0.01) and phosphorus (p<0.05) decreased in fish exposed to terbuthylazine of 60 µg/l and 550 µg/l, while albumin (p<0.01) rised in the same groups. An elevation in natrium (p<0.05) in terbuthylazine of 550 µg/l and a rise in protein (p<0.01) in the concentrations of 380 ng/l and 550 µg/l were observed. Correlations between several indices were significant. Ceruloplasmin activity and FRAP were augmented (p<0.01) in the highest concentration tested. Examined xenobiotic detoxification systems were not significantly affected by the exposure. Non-specific histopathological changes were found in the gills and skin of the test fish.

CONCLUSION: The fish treated with terbuthylazine developed a disorder in several haematological and plasma biochemical indices. The levels of markers of oxidative stress increased in response to the exposure. Examined systems involved in detoxification of xenobiotics did not reflect long-term contact with the herbicide. Detected histological lesions were non-specific. The environmental concentration of terbuthylazin affected biometric indices of the test fish....

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Journal Article 2011; 32(Suppl 1): 25-34 PubMed PMID: 22167217 Citation  Keywords:  Animals, Carcinogens, Environmental:isolation & purification, Cytochrome P-450 CYP1A1:antagonists & inhibitors, DNA Damage:drug effects, Drug Evaluation, Preclinical, Enzyme Induction:drug effects, Enzyme Inhibitors:pharmacology, Food:toxicity, Food Conta.   

OBJECTIVES: Benzo[a]pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogens, which frequently occur in the human diet. Their metabolic activation to reactive species binding to DNA is mediated by cytochromes P450 (CYPs) 1A1 and 1A2. Thus, levels and activities of these CYPs are crucial for initiation of BaP- and PhPI-mediated carcinogenesis. Here, the effect of CYP1A1/2 induction due to their prototype flavonoid inducer, β-naphthoflavone (BNF), on BaP- and PhPI-derived DNA adduct formation in rats was examined.

METHODS: Male rats pretreated with BNF were treated with a single dose of either carcinogen by oral gavage. Nuclease P1 version of 32P-postlabeling assay and online column-switching liquid chromatography-electrospray ionization-tandem mass spectrometry were used to detect and quantify covalent DNA adducts formed by BaP and PhIP in-vivo, respectively. Expression of CYP1A1/2 enzymes was examined by Western blot. Enzymatic activities of CYP1A1/2 were assessed using their marker substrates (ethoxyresorufin and methoxyresorufin).

RESULTS: Treatment of rats with a single dose of BNF produced an increase in levels CYP1A1/2 and CYP1A1 proteins in liver and small intestine, respectively. An increase in CYP1A1 protein expression found in both organs correlated well with specific activities of these CYPs. The CYP1A1 expression levels and its specific activity in small intestine decreased along the length of the organ, being highest in its proximal part and lowest in its distal part. The BNF induction of CYP1A1/2 resulted in a significant increase in the formation of BaP- and PhIP-DNA adducts in liver and in the distal part of the small intestine, respectively. Thus, pretreatment of rats with BNF did not prevent the PhIP and BaP activation, but vice versa, enhanced their genotoxicity.

CONCLUSIONS: The results of this study demonstrate that the administration of only a single dose of CYP-inducing flavonoid prior to the intake of food carcinogens may increase the risk of a tumor formation....

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Journal Article 2011; 32(Suppl 1): 95-100 PubMed PMID: 22167216 Citation  Keywords:  Alkaloids:pharmacology, Animals, Antioxidants:metabolism, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, FMN Reductase:metabolism, Glutathione Reductase:metabolism, Guinea Pigs, Homeostasis:drug effects, Models, Animal, Models, Biological.   

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder. Symptomatic treatment is available by inhibitors of acetylcholinesterase (AChE) such as rivastigmine, galantamine and donepezil. As huperzine is a promising compound for AD treatment, our study was aimed at evaluating its pertinent implications in oxidative stress.

METHODS: Laboratory guinea pigs were exposed to huperzine A at doses of 0, 5, 25, 125 and 625 µg/kg. The animals were observed for cognitive disorders and sacrificed one hour after exposure. Tonic-clonic seizures were noticed, but only in highly dosed animals. Ferric reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), glutathione reductase and glutathione S-transferase were assessed in frontal, temporal and parietal lobes, the cerebellum, liver, spleen and kidney.

RESULTS: Only minimal changes in enzymatic markers were recognized. Huperzine was not implicated in oxidative stress enhancement as the TBARS values remained quite stable. Surprisingly, antioxidants accumulated in the examined brain compartments as the FRAP value was significantly elevated following all doses of huperzine.

CONCLUSIONS: We discuss the potency of huperzine in enhancing the antioxidant capacity of the central nervous system. Huperzine is probably implicated in more processes than cholinesterase inhibition only....

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Journal Article 2011; 32(Suppl 1): 131-136 PubMed PMID: 22167215 Citation  Keywords:  Animals, Dextran Sulfate, Drug Evaluation, Preclinical, Electromyography:methods, Electrophysiological Phenomena:drug effects, Erythromycin:administration & dosage, Female, Gastrointestinal Agents:administration & dosage, Gastrointestinal Diseases:chemica.   

OBJECTIVES: Electrogastrography (EGG) is a non-invasive investigation of gastric myoelectrical activity. The aim of study was to evaluate the impact of erythromycin on EGG in gastrointestinal toxic injury induced by dextran sodium sulphate (DSS) in experimental pigs.

METHODS: The experiments were carried out on 12 adult pigs (weighing 30-35 kg). EGG was recorded using Digitrapper equipment (Synectics Medical AB, Stockholm). Running spectrum activity was used for EGG evaluation. There were two groups of animals: Group I: 6 controls with erythromycin administration (1,600 mg intragastrically); Group II: 6 animals treated with DSS (for 5 days, 0.25 g/kg per day in a dietary bolus) followed by erythromycin administration. Baseline and subsequent six separate 30-minute EGG-recordings (from time 0 to 360 min) were accomplished in each animal.

RESULTS AND CONCLUSION: A total of 84 records were analysed. Baseline dominant frequency of slow waves was fully comparable in both groups. In Group I, there was a significant increase in dominant frequency after erythromycin administration (maximum between 240-360 min). There was a flat non-significant and delayed increase in dominant frequency after erythromycin administration in Group II. The difference between Group I and II at particular time intervals was not significant but a diverse trend was evident. EGG recording enables us to register a gastric myoelectrical effect of prokinetic drugs. Erythromycin induced a significant increase in the dominant frequency of slow waves. DSS caused toxic injury to the porcine gastrointestinal tract responsible for the delayed and weaker myoelectrical effect of erythromycin in experimental animals....

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Journal Article 2011; 32(Suppl 1): 84-88 PubMed PMID: 22167212 Citation  Keywords:  Animals, Blood Cells:drug effects, Carps:blood, Cells, Cultured, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Immunity, Innate:drug effects, Neurotoxins:pharmacology, Phagocytes:drug effects, Pronephros:cytology, Reactive Nitrogen Speci.   

OBJECTIVES: The aim of this study was to determine if cyanoneurotoxin - anatoxin-a (ANTX-a) alters the essential functions of innate immune cells such as free radicals generation in phagocytic cells and phagocytosis.

DESIGN: In the experiments pure ANTX-a was used at concentrations of 0.01, 0.05, 0.1 and 1 µg/ml RPMI-1640 medium. Phagocytes were isolated from carp blood and pronephros. Relative changes in intracellular total free radical presence in fish phagocytes were monitored using a fluorescent probe, dichlorodihydrofluorescin DiOxyQ (DCFH-DiOxyQ) which detects hydrogen peroxide (H2O2), nitric oxide (NO), peroxyl radical and peroxynitrite anion. Phagocytic activity of fish leukocytes was analyzed with a Vybrant phagocytosis assay kit.

RESULTS: The H2O2 level generated in response to ANTX-a at the highest used concentration was significantly suppressed in pronephros but not in blood phagocytes. Moreover, it was observed that generation of superoxide radicals and nitrite formation was significantly increased in blood and pronephros phagocytes after incubation with lower concentrations of the neurotoxin. The phagocytosis of fish leukocytes was significantly reduced at the two highest used toxin concentrations (0.1 and 1 µg/ml medium).

CONCLUSION: This findings suggests that ANTX-a could change innate immunity and reduced adaptive immunity after stress induced by cyanobacterial blooms....

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Comparative Study 2011; 32(Suppl 1): 117-120 PubMed PMID: 22167210 Citation  Keywords:  Animals, Anti-Inflammatory Agents, Non-Steroidal:adverse effects, Cell Membrane Permeability:drug effects, Cyclooxygenase Inhibitors:adverse effects, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Embryo, Nonmammalian, Ketoprofen:adverse .   

OBJECTIVES: Ketoprofen is a common human medicine from a class of non-steroidal anti-inflammatory drugs (NSAIDs), which is provably detected in surface waters in concentrations ordinarily in μg.L-1. The aim of this study was to compare the acute toxicity of ketoprofen to embryonic and juvenile stages of aquarium fish - zebrafish (Danio rerio).

METHODS: Tests were performed according to the methods of the Organisation for Economic Co-operation and Development (OECD) No. 203 (Fish, acute toxicity test) and OECD No. 212 (Fish, short-term toxicity test on embryo and sac-fry stages).

RESULTS: The results showed (mean ± SD) LC50 value of ketoprofen to be 632.30 ± 10.10 mg.L-1 in juvenile zebrafish and 6.44 ± 2.22 mg.L-1 in embryonic stages of zebrafish. The results revealed statistically significantly higher sensitivity (p<0.01) of the embryonic stages of zebrafish to ketoprofen compared to its juveniles. The susceptibility of embryos depends on many factors, especially yet improperly developed enzymatic system in embryos, different ways of the absorption of the substance into the organism or differences in metabolism pathways.

CONCLUSIONS: The acute toxicity of ketoprofen for juvenile stages of zebrafish is low, but the substance seems to be toxic for embryonic stages....

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