RÉSUMÉ
In vivo antigenotoxic activity of BP-C2 composition (at doses of 60, 80, and 120 mg/kg) based on polyphenolic compounds derived from hydrolyzed lignin was evaluated in mouse germ cells. The BP-C2 composition dose-dependently reduced the aneugenic activity of topoisomerase II inhibitor etoposide in mouse oocytes without affecting the clastogenic activity of the genotoxicant. In mouse testicular cells, the BP-C2 composition reduced the DNA-damaging activity of the pro-oxidant genotoxicant dioxidine, but not etoposide. The cytoprotective activity of BP-C2 composition was revealed in relation to etoposide-induced cytotoxicity.
RÉSUMÉ
Topotecan administered intraperitoneally at single doses of 0.25, 0.5, and 1 mg/kg induced chromosomal aberrations in bone marrow cells of F1(CBA×C57BL/6) hybrid mice in a dose-dependent manner. A tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitor, an usnic acid derivative OL9-116 was inactive in a dose range of 20-240 mg/kg, but enhanced the cytogenetic effect of topotecan (0.25 mg/kg) at a dose of 40 mg/kg (per os). The TDP1 inhibitor, a coumarin derivative TX-2552 (at doses of 20, 40, 80, and 160 mg/kg per os), increased the level of aberrant metaphases induced by topotecan (0.25 mg/kg) by 2.1-2.6 times, but was inactive at a dose of 10 mg/kg. The results indicate that TDP1 inhibitors enhance the clastogenic activity of topotecan in mouse bone marrow cells in vivo and are characterized by different dose profiles of the co-mutagenic effects.
Sujet(s)
Cellules de la moelle osseuse , Phosphodiesterases , Topotécane , Animaux , Topotécane/pharmacologie , Souris , Phosphodiesterases/métabolisme , Cellules de la moelle osseuse/effets des médicaments et des substances chimiques , Mâle , Aberrations des chromosomes/effets des médicaments et des substances chimiques , Aberrations des chromosomes/induit chimiquement , Inhibiteurs de la phosphodiestérase/pharmacologie , Inhibiteurs de la topoisomérase-I/pharmacologie , Souris de lignée C57BL , Mutagènes/toxicitéRÉSUMÉ
Parameters of non-spatial and spatial memory were evaluated in sexually mature offspring of outbred rats (females and males F0) consuming a 10% ethanol solution for 30 weeks before mating. We found a significant increase in the recognition index in F1 males and its decrease in F1 females in the novel object recognition test. During the first days of the experiment in T-maze, a decrease in spatial memory was revealed in F1 males, which remained at the trend level until the end of testing; no significant deviations were detected in F1 females. Memory impairment in F1 females was accompanied by a decrease in BDNF level in the hippocampus, but not in the prefrontal cortex. Thus, ethanol consumption by F0 rats before mating led to impairment of long-term working memory only in female F1 offspring.
Sujet(s)
Mémoire à court terme , Reproduction , Mâle , Rats , Femelle , Animaux , Communication cellulaire , Troubles de la mémoire/induit chimiquement , Éthanol/toxicité , HippocampeRÉSUMÉ
Male BALB/c mice with streptozotocin-induced diabetes mellitus were used to study nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) damage using comet DNA assay and real-time PCR, respectively. In animals receiving single injection of streptozotocin in a dose of 200 mg/kg, severe hyperglycemia was observed on days 10 and 21 of the experiment, while after 5-fold administration of streptozotocin in a dose of 40 mg/kg, it developed on days 14 and 28. DNA damage and the level of atypical DNA comets in the liver increased both on days 10 and 21 after single administration of streptozotocin, and on days 14 and 28 after repeated administrations. The level of atypical DNA comets on day 21 after a single administration of streptozotocin increased in the kidneys, but not in the brain, testes, and pancreas. Real-time PCR revealed mtDNA damage in the liver, kidney, and pancreatic cells of mice with streptozotocin-induced diabetes. Thus, these animal models were found to reproduce pathognomic signs of diabetes, hyperglycemia, and nDNA damage; mtDNA damage was also detected.
Sujet(s)
Diabète expérimental , Hyperglycémie , Souris , Mâle , Animaux , ADN mitochondrial/génétique , Streptozocine , Souris de lignée BALB C , Hyperglycémie/induit chimiquement , Hyperglycémie/génétique , Diabète expérimental/induit chimiquement , Diabète expérimental/génétique , Altération de l'ADNRÉSUMÉ
We studied the effects of polyphenolic composition BP-C2, comprising molybdenum with lignin derivatives, on lung carcinogenesis induced by urethane in the progeny of F0 male BALB/c mice preconceptionally exposed to radiation in a dose of 1 Gy. The multiplicity of lung tumors in the progeny of irradiated mice was higher than in the progeny of non-irradiated male parents by 50% in females and 43% in males (p<0.05). In F1 mice (progeny of irradiated F0 male parents treated with BP-C2), the multiplicity of lung tumors was also higher, but this increase was less pronounced: 35% in females (p=0.3852) and 23% in males (p=0.0766). We have demonstrated that administration of BP-C2 to irradiated parents (F0) efficiently inhibits carcinogenesis in their F1 progeny. The use of BP-C2 in irradiated male parents and their progeny not only reduced the multiplicity of tumors, but also normalized body weights in the F1 progeny. Our study demonstrates potential of the polyphenolic composition BP-C2 for chemoprophylaxis of radiation-induced transgenerational carcinogenesis.
Sujet(s)
Tumeurs du poumon , Uréthane , Femelle , Mâle , Souris , Animaux , Uréthane/effets indésirables , Souris de lignée BALB C , Cancérogènes , Carcinogenèse , Amides , Tumeurs du poumon/induit chimiquement , Tumeurs du poumon/prévention et contrôle , Agents protecteurs , PoumonRÉSUMÉ
The analysis of experimental data on the study of the genotoxic activity of psychotropic drugs published over the past 25 years has been carried out. It has been shown that the information describing the genotoxicity of psychotropic drugs is characterized by fragmentation, contradictions, and the conditions for their experimental production often do not meet modern requirements. Conclusions about the presence or absence of genotoxic properties can be made only for 9.6% 94 examined drugs. The need for a large-scale systematic reassessment of the genotoxicity of psychotropic drugs, especially drugs of the first generation, on the basis of modern methodology, including studies of mutagen-modifying activity, has been proven. The expediency of monitoring the genotoxic status of patients receiving psychotropic drugs is emphasized, which should contribute to an adequate assessment of the genotoxic risk of their use and objectification of approaches when choosing a drug for the safe therapy. The urgency of conducting research to determine the role of primary DNA damage in the pathogenesis of mental illnesses has been substantiated.
Sujet(s)
Altération de l'ADN , Mutagènes , Humains , Psychoanaleptiques/effets indésirablesRÉSUMÉ
The study examined the effect of GTS-201, a low-molecular weight mimetic of brain-derived neurotrophic factor (BDNF) loop 2, on persistent alcohol craving in outbred male and female albino rats with ethanol preference score ~50% developed in the free choice paradigm between 10% ethanol and water over 24 weeks. Both single and subchronic (5 days) injections of GTS-201 in a daily dose of 5 µg/kg reduced alcohol deprivation effect in female, but not in male rats. The possibility of in vivo sex-dependent regulation of modeled alcohol craving with a low-molecular-weight dipeptide mimetic of BDNF loop 2 was demonstrated and sex-related differences in this effect were revealed.
Sujet(s)
Consommation d'alcool/prévention et contrôle , Facteur neurotrophique dérivé du cerveau/pharmacologie , Consommation d'alcool/anatomopathologie , Alcoolisme/traitement médicamenteux , Alcoolisme/anatomopathologie , Animaux , Lignées animales non consanguines , Matériaux biomimétiques/composition chimique , Matériaux biomimétiques/pharmacologie , Facteur neurotrophique dérivé du cerveau/usage thérapeutique , Éthanol/administration et posologie , Femelle , Mâle , Masse moléculaire , Rats , Caractères sexuelsRÉSUMÉ
The existing concepts of antimutagenesis are briefly reviewed. Published reports on antimutagenic and proapoptotic properties of some polyphenols and compounds of other chemical groups obtained in representative in vitro and in vivo experiments on eukaryotic test systems are discussed. The relationships between the antimutagenic and proapoptotic properties of the analyzed compounds (naringin, apigenin, resveratrol, curcumin, N-acetylcysteine, etc.) are considered in favor of the hypothesis on induced cell death as an antimutagenic tool.
Sujet(s)
Antimutagènes , Acétylcystéine , Antimutagènes/pharmacologie , Mort cellulaireRÉSUMÉ
The anxiolytic and analgesic properties of compound ALM-802, a cardiotropic linear methoxyphenyltriazaalkane derivative, combining pharmacophore elements of p-FOX inhibitors trimetazidine and ranolazine were studied in vivo. In the elevated plus-maze test, ALM-802 after acute intraperitoneal administration in doses of 1-8 mg/kg dose-dependently prevented the development of anxiety in BALB/c mice. Chronic intraperitoneal administration of ALM-802 in a dose of 2 mg/kg to alcohol-preferring rats attenuated anxiogenesis induced by ethanol withdrawal. ALM-802 demonstrated antinociceptive activity in C57BL/6 mice during thermal stimulation of nociceptors in the hot plate test and during modeling of visceral pain in the acetic acid writhing test. Thus, ALM-802 exhibits anxiolytic and analgesic properties in the dose range corresponding to its anti-ischemic and antiarrhythmic effects.
Sujet(s)
Nociception/effets des médicaments et des substances chimiques , Trimétazidine/usage thérapeutique , Animaux , Anxiété/traitement médicamenteux , Anxiété/métabolisme , Mâle , Souris , Souris de lignée BALB C , Souris de lignée C57BL , Nocicepteurs/métabolisme , Douleur/traitement médicamenteux , Douleur/métabolismeRÉSUMÉ
In vitro experiments performed on an isolated human endothelial HUVEC cell culture showed that the anxiolytic fabomotizole, which, in addition to the anxiolytic effect, has neuroprotective and cardioprotective activities largely associated with its agonistic action on sigma-1 receptors and shows a pronounced angiogenic activity. Fabomotizole angiogenic activity is realized in the range concentration from 10-5 to 10-8 M and is doze-dependent. In the literature, data on the presence of angiogenic activity in sigma receptor agonists have not been previously reported.
Sujet(s)
Anxiolytiques/pharmacologie , Benzimidazoles/pharmacologie , Morpholines/pharmacologie , Mouvement cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Cellules endothéliales de la veine ombilicale humaine/cytologie , Cellules endothéliales de la veine ombilicale humaine/effets des médicaments et des substances chimiques , Cellules endothéliales de la veine ombilicale humaine/métabolisme , Humains , Récepteur sigma/métabolisme ,RÉSUMÉ
The effects of 5-hydroxypyrimidine derivatives SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine chlorohydrate) on the tumor growth and survival of male C57BL/6 mice with transplanted Lewis lung epidermoid carcinoma (LLC) were studied in animals receiving intraperitoneal treatment on days 2-15 of tumor development. Compound SNK-578 in a dose of 10 mg/kg significantly inhibited tumor growth (by 3.6 times; 72.2%) in 7 days after the treatment was discontinued, while compound SNK-411 in a dose of 25 mg/kg only negligibly reduced tumor volume (by 41.7%). A combination of course of SNK-411 (25 mg/kg) and single intraperitoneal dose of doxorubicin (4 mg/kg) significantly inhibited the tumor growth (by 2.2 times; 55.2%), while the combination of SNK-578 (10 mg/kg) with doxorubicin (4 mg/kg) was in fact ineffective. The median survival of animals with untreated LLC was 28 days. Median survival of mice injected with SNK-578 (10 mg/kg) was 43 days, hence, the lifespan of mice with LLC was by 38.6% longer after the treatment. Two of ten mice in this group developed no tumors.
Sujet(s)
Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Carcinome pulmonaire de Lewis/traitement médicamenteux , Tumeurs du poumon/traitement médicamenteux , Pyrimidines/composition chimique , Animaux , Doxorubicine/usage thérapeutique , Longévité/effets des médicaments et des substances chimiques , Mâle , Souris , Souris de lignée C57BL , Pyrimidines/usage thérapeutique , Charge tumorale/effets des médicaments et des substances chimiquesRÉSUMÉ
In experiments on BALB/c mice, prediabetes was modeled by administration of streptozotocin in a dose of 130 mg/kg. DNA damage was assessed by the method of DNA comets. Noopept (0.5 mg/kg intraperitoneally) was administered for 14 days before and for 6, 13, or 14 days after streptozotocin administration. Despite moderate hyperglycemia and increased malondialdehyde level, the intensity of DNA damage in cells of the pancreas, liver, and kidneys significantly surpassed the control values. Noopept normalized these parameters due to its pronounced antigenotoxic effect. For both the damaging effect of streptozotocin and the normalizing effect of Noopept, DNA changes manifested mainly in terms of atypical DNA comets. Our findings confirm the role of DNA damage in the pathogenesis of diabetes. They indicate the possibility of pharmacological protection of pancreatic ß cells with the neuroprotective drug and provide an important argument in favor of the hypothesis about the similarity of the mechanisms of formation of the resistance of neurons and ß cells to the cytotoxic influences.
Sujet(s)
Altération de l'ADN/effets des médicaments et des substances chimiques , Dipeptides/pharmacologie , Cellules à insuline/anatomopathologie , Neuroprotecteurs/pharmacologie , État prédiabétique/génétique , Animaux , Glycémie/analyse , Diabète expérimental/anatomopathologie , Hyperglycémie/anatomopathologie , Rein/anatomopathologie , Foie/anatomopathologie , Mâle , Malonaldéhyde/sang , Souris , Souris de lignée BALB C , StreptozocineRÉSUMÉ
The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.05) and prevented the formation of ethanol-induced memory and attention disturbances (p<0.01) developing during alcohol withdrawal. In ex vivo experiments, Selank prevented ethanol-induced increase in BDNF content in the hippocampus and frontal cortex (p<0.05). These results indicate positive effects of the tuftsin analogue on age-related memory disturbances associated with chronic alcohol intoxication and confirm the involvement of the neurotrophin mechanism related to BDNF production into the effect of Selank.
Sujet(s)
Anxiolytiques/pharmacologie , Facteur neurotrophique dérivé du cerveau/génétique , Hippocampe/effets des médicaments et des substances chimiques , Troubles de la mémoire/prévention et contrôle , Nootropiques/pharmacologie , Oligopeptides/pharmacologie , Cortex préfrontal/effets des médicaments et des substances chimiques , Alcoolisme/traitement médicamenteux , Alcoolisme/étiologie , Alcoolisme/métabolisme , Alcoolisme/physiopathologie , Animaux , Lignées animales non consanguines , Anxiolytiques/synthèse chimique , Facteur neurotrophique dérivé du cerveau/agonistes , Facteur neurotrophique dérivé du cerveau/antagonistes et inhibiteurs , Facteur neurotrophique dérivé du cerveau/métabolisme , Éthanol/administration et posologie , Expression des gènes/effets des médicaments et des substances chimiques , Hippocampe/métabolisme , Hippocampe/physiopathologie , Mâle , Troubles de la mémoire/induit chimiquement , Troubles de la mémoire/métabolisme , Troubles de la mémoire/physiopathologie , Mémoire à court terme/effets des médicaments et des substances chimiques , Nootropiques/synthèse chimique , Oligopeptides/synthèse chimique , Cortex préfrontal/métabolisme , Cortex préfrontal/physiopathologie , Rats , Tuftsine/composition chimique , Tuftsine/métabolismeRÉSUMÉ
We created a translational model of chronic heart failure in rats that developed in 3 months after reproducing experimental anterior transmural myocardial infarction. The model simulated the basic clinicodiagnostic criteria of this disease: impaired contractility and dilatation of heart ventricles, signs of venous congestion, elevated plasma content of biochemical markers, and abnormal overexpression of AT1aR and ß-adrenoceptors.
Sujet(s)
Modèles animaux de maladie humaine , Défaillance cardiaque/physiopathologie , Ventricules cardiaques/physiopathologie , Infarctus du myocarde/physiopathologie , Myocarde/anatomopathologie , Animaux , Lignées animales non consanguines , Marqueurs biologiques/métabolisme , Échocardiographie , Expression des gènes , Défaillance cardiaque/imagerie diagnostique , Défaillance cardiaque/génétique , Défaillance cardiaque/métabolisme , Ventricules cardiaques/imagerie diagnostique , Ventricules cardiaques/métabolisme , Hémodynamique/physiologie , Humains , Mâle , Contraction myocardique/physiologie , Infarctus du myocarde/imagerie diagnostique , Infarctus du myocarde/génétique , Infarctus du myocarde/métabolisme , Myocarde/métabolisme , ARN messager/génétique , ARN messager/métabolisme , Rats , Récepteur de type 1 à l'angiotensine-II/génétique , Récepteur de type 1 à l'angiotensine-II/métabolisme , Récepteurs bêta-1 adrénergiques/génétique , Récepteurs bêta-1 adrénergiques/métabolisme , Récepteurs bêta-2 adrénergiques/génétique , Récepteurs bêta-2 adrénergiques/métabolisme , /méthodesRÉSUMÉ
Antiviral drug Kagocel in concentrations of 0.0008, 0.004, 0.02, 0.1, 0.5, and 2.5 mg/ml with or without metabolic activation does not induce gene mutations in S. typhimurium strains ТÐ98, ТÐ100, ТÐ1535, and ТÐ1537 and in a combination of E. coli strains pKM101 and uvrA. A single intragastric administration of Kagocel in a daily therapeutic dose and a 10-fold daily therapeutic dose to male mice or multiple administrations in daily therapeutic dose to male and female mice did not led to a significant increase in the percentage of chromosomal aberrations in the bone marrow cells. DNA comet assay revealed no significant increase in the incidence of DNA breaks in cells of mouse testes after single or multiple administration of Kagocel at daily therapeutic and 10-fold daily therapeutic doses. Our results indicate that Kagocel exhibits no genotoxic activity in the studied dose range.
Sujet(s)
Antiviraux/pharmacologie , Gossypol/analogues et dérivés , Tests de toxicité aigüe , Tests de toxicité chronique , Animaux , Moelle osseuse/composition chimique , Moelle osseuse/effets des médicaments et des substances chimiques , Aberrations des chromosomes , Test des comètes , Croisements génétiques , Fragmentation de l'ADN/effets des médicaments et des substances chimiques , Calendrier d'administration des médicaments , Escherichia coli/effets des médicaments et des substances chimiques , Escherichia coli/génétique , Femelle , Gossypol/pharmacologie , Mâle , Souris , Souris de lignée C57BL , Souris de lignée CBA , Salmonella typhimurium/effets des médicaments et des substances chimiques , Salmonella typhimurium/génétiqueRÉSUMÉ
We studied antidiabetic effects and cytoprotective activity of two lithium salts (lithium chloride and lithium carbonate) on the model of streptozotocin-induced diabetes mellitus type 2 in Wistar rats. Using the method of ß-cells detection with antibodies to insulin, we demonstrated that streptozotocin reduced the number of ß-cells and impaired their morphological structure. Both lithium preparations administered to diabetic animals for 28 days in doses of 10 and 8.9 mg/kg, respectively, attenuated the damaging effect of streptozotocin. This cytoprotective effect of lithium salts manifested in weakening of hyperglycemia, polyphagia, polydipsia, and weight loss. A satisfactory correlation between the morphometric data and blood glucose levels was revealed. The mechanisms of the multitarget action of lithium salts are discussed.
Sujet(s)
Cellules à insuline/effets des médicaments et des substances chimiques , Carbonate de lithium/pharmacologie , Chlorure de lithium/pharmacologie , Neuroprotecteurs/pharmacologie , Animaux , Glycémie , Diabète de type 2/induit chimiquement , Diabète de type 2/traitement médicamenteux , Immunohistochimie , Insuline/sang , Foie/anatomopathologie , Mâle , Rats , Rat Wistar , StreptozocineRÉSUMÉ
We developed a translation model of alcoholic cardiomyopathy in rats. By the end of forced alcoholization (the rats received 10% ethanol solution as the only source of fluid for 24 weeks; mean daily ethanol consumption was 5.0-6.5 g/kg), the rats developed dilated heart failure. Echocardiography and morphometric study of the myocardium revealed a decrease in inotropic function of the heart and dilatation of the right and left ventricles. Fatty degeneration of the myocardium (pathognomonic sign of alcoholic cardiomyopathy) and decrease in electrical stability of cardiomyocytes reliably reproduce the clinical pattern of alcoholic cardiomyopathy.
Sujet(s)
Cardiomyopathie alcoolique/imagerie diagnostique , Échocardiographie/méthodes , Animaux , Cardiomyopathie alcoolique/anatomopathologie , Modèles animaux de maladie humaine , Éthanol/toxicité , Coeur/physiopathologie , Mâle , Myocarde/anatomopathologie , Rats , Rat WistarRÉSUMÉ
Aneugenic effects of the chemicals with antitumor activity were studied in mouse oocytes in vivo by cytogenetic analysis. In control mice, no oocytes with numerical chromosome aberrations were found. Colchicine (0.2-4 mg/kg), paclitaxel (2.5-7.5 mg/kg), and etoposide (10-60 mg/kg) produced a significant dose-dependent aneugenic effects (induction of up to 25% aneuploid oocytes) and increased the yield of oocytes arrested in the meiotic MI stage and with premature separation of sister chromatid. Paclitaxel induced up to 20% polyploid chromosomes. Doxorubicin (2.5 mg/kg), melphalan (10 mg/kg), and cisplatin (5-10 mg/kg) exhibited weak aneugenic activity (induction of up to 5% aneuploid oocytes). Cyclophosphamide (10-80 mg/kg) had minor effect on the studied parameters. Methotrexate (25-200 mg/kg) exhibited no aneugenic activity, but significantly increased the level of polyploid cells. The observed aneugenic effects included hypo- and hyperploidy in various proportions or hypoploidy, but no solely hyperhaploidy.
Sujet(s)
Doxorubicine/pharmacologie , Aneugènes , Aneuploïdie , Animaux , Cisplatine/pharmacologie , Colchicine/pharmacologie , Étoposide/pharmacologie , Melphalan/pharmacologie , Souris , Ovocytes/effets des médicaments et des substances chimiques , Ovocytes/métabolisme , Paclitaxel/pharmacologie , PolyploïdieRÉSUMÉ
The phenomenon of atypical DNA comets in experiments using DNA comet assay is described and illustrated. The current hypotheses explaining the nature of atypical DNA comets and own vision of the issue are considered. The practical importance of the registration of atypical DNA comets in assessing the genotoxicity is discussed.
Sujet(s)
Test des comètes/méthodes , Altération de l'ADN , ADN/composition chimique , Animaux , ADN/métabolisme , HumainsRÉSUMÉ
Cognitive activity in 60-day-old offspring of rats (intrauterine development in experimental streptozotocin-induced diabetes) was studied on the model of food-seeking behavior under conditions of free choice in a 6-arm maze. The formation of the food-procuring skill was significantly delayed, which attests to impairment of cognitive functions in these animals. Peroral administration of afobazole (10 and 50 mg/kg) and betaine (50 and 100 mg/kg) significantly and dose-dependently alleviated this disorder. Correlation analysis of the data on delayed formation of a food-procuring skill and results of DNA comet attests to a strong relationship between DNA damage in cells of the embryo and placenta during intrauterine development and cognitive dysfunction in the postnatal offspring of animals with streptozotocin-induced diabetes.