RESUMO
Eating diets high in salt has been associated with alterations in the immune system and the potential development of neuropsychiatric disorders. This area of research shows promise, but there is currently a limited amount of research on this topic. The present study investigated whether a high salt diet (HSD) affects anhedonia and stress-coping response behaviors in young male and female Wistar rats. In this study, male and female Wistar rats were fed an HSD (8 % NaCl w/w) from weaning to post-natal day (PND) 64. From PND 60 to 64, the rats underwent a spontaneous locomotor activity test (SLA), sucrose splash test (SST), sucrose preference test (SPT), and forced swim test (FST), followed by euthanasia at PND 65. Male and female rats consuming the HSD exhibited an increase in water intake compared to the corresponding control diet (CD) groups. Male rats had lower body weight despite having similar food intakes compared to the CD group. Male rats displayed an active stress-coping behavior in the FST, characterized by increased mobility. Additionally, HSD-fed males exhibited a greater preference for sucrose solution in the SPT. However, no effect of diet and sex were detected in the SST and the SLA, and hypothalamic levels of leptin and ghrelin receptors. On the other hand, female rats were less susceptible to the experimental conditions applied in this protocol than males.
Assuntos
Capacidades de Enfrentamento , Cloreto de Sódio na Dieta , Ratos , Animais , Masculino , Feminino , Ratos Wistar , Peso Corporal/fisiologia , SacaroseRESUMO
Sports-related concussions are particularly common during adolescence, and there is insufficient knowledge about how recurrent concussions in this phase of life alter the metabolism of essential structures for memory in adulthood. In this sense, our experimental data revealed that seven recurrent concussions (RC) in 35-day-old rats decreased short-term and long-term memory in the object recognition test (ORT) 30 days after injury. The RC protocol did not alter motor and anxious behavior and the immunoreactivity of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Recurrent concussions induced the inflammatory/oxidative stress characterized here by increased glial fibrillary acidic protein (GFAP), interleukin 1ß (IL 1ß), 4-hydroxynonenal (4 HNE), protein carbonyl immunoreactivity, and 2',7'-dichlorofluorescein diacetate oxidation (DCFH) levels and lower total antioxidant capacity (TAC). Inhibited Na+,K+-ATPase activity (specifically isoform α2/3) followed by Km (Michaelis-Menten constant) for increased ATP levels and decreased immunodetection of alpha subunit of this enzyme, suggesting that cognitive impairment after RC is caused by the inability of surviving neurons to maintain ionic gradients in selected targets to inflammatory/oxidative damage, such as Na,K-ATPase activity.
Assuntos
Concussão Encefálica , Disfunção Cognitiva , Hipocampo , Transtornos da Memória , Doenças Neuroinflamatórias , Estresse Oxidativo/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Memória Espacial/fisiologia , Fatores Etários , Animais , Concussão Encefálica/complicações , Concussão Encefálica/imunologia , Concussão Encefálica/metabolismo , Concussão Encefálica/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Hipocampo/imunologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/imunologia , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/fisiopatologia , Ratos , Ratos WistarRESUMO
Bovine alphaherpesvirus 2 (BoHV-2) - the agent of bovine herpetic mamillitis (BHM) - is related to Human alphaherpesviruses 1 and 2 (HHV-1, HHV-2) and, as such, has been proposed as a model for vaccine and drug testing. We herein investigated the anti-viral activity in vitro against BoHV-2 of three anti-herpetic drugs: Cidofovir (CDV), Fanciclovir (FAM), Foscarnet (PFA), and diphenyl disselenide (Ph2Se2), a compound that has showed activity against HHV-2. Plaque reduction assays (PRA) revealed a significant reduction in viral plaques (p < 0.05) in cells treated with Ph2Se2 (79.7% reduction) or CDV (62.8%). FAM treatment resulted in a slight decrease in plaque number (22.9%, p < 0.05); PFA showed no activity. The effects of Ph2Se2 and CDV, alone or in combination, were investigated in ewes inoculated with BoHV-2 transdermally and submitted to daily topic treatment. Virus inoculated ewes developed lesions progressing through the stages of hyperemia, large papules or depressed dark areas, followed by scab formation. Treatment with Ph2Se2 resulted in reduction in clinical score from day 10 pi onwards (P < 0.05), shortening of clinical course and reduction in duration of virus shedding (P < 0.05) compared to untreated controls. Combined treatment (Ph2Se2 + CDV) and CDV alone, also led to clinical improvement (P < 0.05), yet less pronounced and delayed. These results are promising towards the use of Ph2Se2, alone or in combination with anti-herpetic drugs, in the treatment of udder and teat lesions produced by BoHV-2 in dairy cows.
Assuntos
Antivirais/farmacologia , Derivados de Benzeno/farmacologia , Cidofovir/farmacologia , Herpes Simples/veterinária , Herpesvirus Bovino 2/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Doenças dos Ovinos/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Derivados de Benzeno/uso terapêutico , Cidofovir/uso terapêutico , Feminino , Herpes Simples/tratamento farmacológico , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/virologia , Compostos Organosselênicos/uso terapêutico , Ovinos , Doenças dos Ovinos/virologia , Eliminação de Partículas Virais/efeitos dos fármacosRESUMO
Amphetamine (AMPH) abuse is a world concern and a serious public health problem. Repeated administration of high doses of AMPH induces neuropsychiatric consequences, including addiction, reward and psychosis, whose pharmacological treatment has shown limited effectiveness. The m-trifluoromethyl-diphenyldiselenide [(m-CF3-PhSe)2] has been documented as a promising pharmacological agent in different animal models related to oxidative damage. In this study, we examined the influence of (m-CF3-PhSe)2 on withdrawal following re-exposure to AMPH. Wistar rats received d,l-AMPH or saline in the conditioned place preference (CPP) paradigm for 8days. Then, half of each initial (AMPH or saline) experimental group was treated with (m-CF3-PhSe)2 or vehicle, resulting in four final groups: i) Saline/vehicle; ii) (m-CF3-PhSe)2/saline; iii) AMPH/vehicle; and iv) AMPH/(m-CF3-PhSe)2. After fourteen days of (m-CF3-PhSe)2 treatment, animals were re-exposed to AMPH or vehicle in the CPP paradigm for three more days in order to assess drug re-conditioning and memory/locomotor activity, performed 24h after AMPH re-exposure in the CPP and the Y maze, respectively. Subsequently, ex-vivo assays were carried out in samples of the prefrontal cortex (PFC) of the animals. The (m-CF3-PhSe)2 treatment was able to prevent AMPH-induced re-conditioning symptoms in rats. Behavioral observations in the Y maze task showed no significant changes. AMPH exposure was able to increase 5-HT uptake as well as oxidative damage in the PFC, whereas (m-CF3-PhSe)2 treatment exerted a preventative effect against these alterations. The current findings suggest that (m-CF3-PhSe)2 might be considered a promising therapeutic tool for AMPH-induced addiction.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Anfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Compostos de Organossilício/farmacologia , Síndrome de Abstinência a Substâncias , Animais , Aprendizagem por Associação/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
This study was designed to investigate the molecular effects of diphenyl diselenide ((PhSe)2) on cholesterol metabolism in HepG2 cell line in a dose-dependent manner. The protein levels of both total and phosphorylated 3- hydroxy-3-methylglutaryl coenzyme A reductase (HMGR and P-HMGR), low-density lipoprotein receptors (LDLr) and the proteins involved in their regulatory network were analyzed by Western blotting, and the effect of (PhSe)2 on HMGR activity was measured. Additionally, we also evaluated the effects of this compound on glucose transporter type 4 (GLUT4) translocation using fluorescence microscopy in L6 skeletal muscle cell line. Results demonstrated that (PhSe)2 increased P-HMGR, HMGR, and LDLr protein levels as well as simvastatin treatment, which was used as positive control, without directly affecting HMGR activity. We observed that both long- and short-term HMGR regulation mechanisms are involved in the effects of (PhSe)2, as this compound was able to augment Sterol regulatory element binding proteins (SREBP)-1 and Insulin induced gene (Insig)1 protein levels, and to increase AMP activated kinase (AMPK) activation state. We also found that, in L6 skeletal myotubes, 10 µM (PhSe)2 increases GLUT4 translocation through AMPK activation. Taken together, these findings suggest that (PhSe)2 can modulate the expression of some proteins involved in cholesterol and glucose cell metabolism.
Assuntos
Derivados de Benzeno/farmacologia , Colesterol/metabolismo , Glucose/metabolismo , Músculo Esquelético/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Western Blotting , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Imunofluorescência , Transportador de Glucose Tipo 4/metabolismo , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Estrutura Molecular , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Fosforilação , Transporte Proteico/efeitos dos fármacos , Ratos , Receptores de LDL/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismoRESUMO
In this study, we investigated the effects of 2,2'-dithienyl diselenide (DTDS), an organoselenium compound, against seizures induced by kainic acid (KA) in rats. Rats were pretreated with DTDS (50 or 100 mg/kg) by oral route 1 h before KA injection (10 mg/kg, intraperitoneal). Our results showed that DTDS (100 mg/kg) was effective in increasing latency for the onset of the first clonic seizure episode induced by KA, as well as in decreasing the appearance of seizures and the Racine's score. DTDS also caused a decrease in the excitatory electroencephalographic (EEG) changes, resulting from KA exposure in hippocampus and cerebral cortex of rats. Besides, elevated reactive species (RS) and carbonyl protein levels and Na(+), K(+)-ATPase activity in hippocampus of rats treated with KA were ameliorated by DTDS (50 and 100 mg/kg). Lastly, as evidenced by Cresyl-Violet stain, DTDS (100 mg/kg) elicited a protective effect against KA-induced neurodegeneration in rat hippocampus 7 days after KA injection. In conclusion, the present study showed that DTDS attenuated KA-induced status epilepticus in rats and the subsequent hippocampal damage.
Assuntos
Hipocampo/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/prevenção & controle , Compostos Organosselênicos/uso terapêutico , Tiofenos/uso terapêutico , Timidina/análogos & derivados , Compostos de Tritil/uso terapêutico , Análise de Variância , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletroencefalografia , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Caínico/toxicidade , Masculino , Fármacos Neuroprotetores/química , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/etiologia , Neurotoxinas/toxicidade , Compostos Organosselênicos/química , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Convulsões/etiologia , Convulsões/prevenção & controle , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Sulfidrila/metabolismo , Tiofenos/química , Timidina/química , Timidina/uso terapêutico , Compostos de Tritil/químicaRESUMO
Organoselenium compounds display important antioxidant activity and many biological activities interesting from pharmacological point of view. The aim of this study was to evaluate the hepatoprotective effect of p-methoxyl-diphenyl diselenide, a disubstituted diaryl diselenide, on acute liver injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) in mice. The animals received p-methoxyl-diphenyl diselenide (10, 50 and 100 mg/kg; per oral, p.o.) and 1 h after d-GalN (500 mg/kg) and LPS (50 microg/kg) were administered by intraperitoneal route (i.p.). Twenty-four hours after LPS/d-GalN exposure the animals were euthanized to the biochemical and histological analysis. Pretreatment with p-methoxyl-diphenyl diselenide (50 and 100 mg/kg; p.o.) protected against the increase in aspartate aminotransferase (AST) activity induced by LPS/d-GalN exposure in mice. p-Methoxyl-diphenyl diselenide at the doses of 50 and 100 mg/kg protected against the increase in alanine aminotransferase (ALT) activity induced by LPS/D-GalN exposure. In this study, no alteration in ascorbic acid levels was observed in livers of mice exposed to LPS/D-GalN. Glutathione-S-transferase (GST) activity was stimulated by LPS/D-GalN exposure and p-methoxyl-diphenyl diselenide, at all doses, protected against this alteration. p-Methoxyl-diphenyl diselenide was effective in ameliorating inhibition of catalase activity induced by LPS/d-GalN exposure. Histological data showed that sections of livers from LPS/D-GalN-treated mice presented massive hemorrhage, inflammatory cells and necrosis. p-Methoxyl-diphenyl diselenide significantly attenuated LPS/D-GalN-induced hepatic histopathological alterations. Based on the results, we suggest the hepatoprotective effect of p-methoxyl-diphenyl diselenide on acute liver injury induced by LPS/d-GalN exposure in mice.
Assuntos
Antioxidantes/uso terapêutico , Derivados de Benzeno/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Falência Hepática Aguda/prevenção & controle , Compostos Organosselênicos/uso terapêutico , Administração Oral , Alanina Transaminase/metabolismo , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/metabolismo , Aspartato Aminotransferases/metabolismo , Derivados de Benzeno/farmacologia , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Relação Dose-Resposta a Droga , Galactosamina , Glutationa Transferase/metabolismo , Injeções Intraperitoneais , Lipopolissacarídeos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Masculino , Camundongos , Compostos Organosselênicos/farmacologiaRESUMO
DNA damage and cell viability of human leukocytes cells were examined as simple tests for screening the potential toxicity of organoselenium compounds. Leukocytes were incubated with different organoselenium compounds at 4, 10, 40 and 100 microM or vehicle (DMSO) for 3h at 37 degrees C before of in vitro assays. Cell viability was determined by Trypan blue exclusion. DNA damage was assessed using the alkaline comet assay with silver staining. The exposure of leukocytes to (S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate, (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate, (S)-2-amino-1-diselenide-3-methylpropanyl, (S)-2-amino-1-diselenide-3-phenylpropanyl, 3',3-ditrifluoromethyl diphenyl diselenide, 4',4-dimethoxy diphenyl diselenide, 4',4-dichloro diphenyl diselenide and 2',2,4',4,6',6-hexamethyl diphenyl diselenide, in the range of 10-100muM, induced a significant increase in Damage Index (DI). The genotoxic effect of all compounds was associated with high frequencies of cells with damage level 4 and all compounds caused a decrease in cell viability. Our results suggest that the selenium compounds tested were genotoxic and cytotoxic to human leukocytes cells in vitro and that the organoselenium amino acid derivatives ((S)-tert-butyl 1-diselenide-3-methylbutan-2-ylcarbamate, (S)-tert-butyl 1-diselenide-3-phenylpropan-2-ylcarbamate, (S)-2-amino-1-diselenide-3-methylpropanyl and (S)-2-amino-1-diselenide-3-phenylpropanyl) were more genotoxic than aromatic derivatives (3',3-ditrifluoromethyl diphenyl diselenide, 4',4-dimethoxy diphenyl diselenide, 4',4-dichloro diphenyl diselenide and 2',2,4',4,6',6-hexamethyl diphenyl diselenide). These effects may be linked to the pro-oxidant activity exhibited by selenium compounds when used in relatively high concentrations.
Assuntos
Dano ao DNA/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Testes de Mutagenicidade/normas , Compostos Organosselênicos/farmacologia , Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Dano ao DNA/genética , Sequestradores de Radicais Livres/farmacologia , Humanos , Contagem de Leucócitos/métodos , Leucócitos/metabolismo , Compostos Organosselênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/farmacologia , Compostos de Selênio/farmacologiaRESUMO
Cigarette smoke is a complex mixture of various toxic substances that are capable of initiating oxidative damage and promoting blood platelet alterations. In this study, we investigated the activities of the ectoenzymes NTPDase (ectonucleoside triphosphate diphosphohydrolase, CD39) and 5'-nucleotidase (CD73) in platelets as well as adenosine deaminase (ADA) in the plasma of rats exposed to aged and diluted sidestream smoke during 4 weeks. The rats were divided into two groups: I (control) and II (exposed to smoke). After the exposure period, blood was collected and the platelets and plasma were separated for enzymatic assay. The results demonstrated that NTPDase (with ATP as substrate) and 5'-nucleotidase (AMP as substrate) activities were significantly higher in group II (p < 0.05) as compared to group I, while no significant difference was observed for NTPDase with ADP as substrate. The ADA activity was significantly reduced in group II (p < 0.05) as compared with group I. Platelet aggregation was significantly increased in group II (p < 0.05) as compared with group I. We suggest that these alterations in the activity of enzymes from the purinergic system are associated with an increase in platelet aggregation. However, our study has demonstrated that the organism tries to compensate for this enhanced aggregation by increasing hydrolysis of AMP and reducing hydrolysis of adenosine, a potent inhibitor of aggregation and an important modulator of vascular tone.
Assuntos
Adenosina Desaminase/metabolismo , Adenosina Trifosfatases/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , 5'-Nucleotidase/sangue , Adenosina/sangue , Animais , Gasometria , Plaquetas/enzimologia , Carboxihemoglobina/metabolismo , Concentração de Íons de Hidrogênio , Pulmão/enzimologia , Pulmão/patologia , Masculino , Agregação Plaquetária/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Ratos , Ratos Wistar , Nicotiana/químicaRESUMO
This study investigated the hemolytic and genotoxic effect of different organoselenium and organotellurium compounds in human blood cells, as simple tests for screening the toxicity of organochalcogenides. For osmotic fragility (OF) test, samples of total blood were incubated with the organochalcogens at 4, 8, 50, 75 and 100 microM or vehicle (DMSO) for 90 min at 37 degrees C. The EC(50) values for hemolysis were significantly increased in erythrocytes exposed to diphenyl selenide (II), diphenyl diselenide (III), diphenyl telluride (IV), diphenyl ditelluride (V), (S)-2-amino-1-diselenide-3-methylpropanyl (IX), butyl(styryl)telluride (XIII) and 2-(butyltellurium)furan (XIV) at higher concentrations tested. The exposure of erythrocytes to organochalcogens diphenyl diselenide (II) and butyl(styryl)telluride (XIII), which had greater hemolytic effect, did not modify catalase activity, reactive oxygen species (ROS) production and -SH content. On the other hand, Na(+)/K(+) ATPase activity of erythrocyte ghosts was significantly inhibited by the compounds diphenyl diselenide (II) and butyl(styryl)telluride (XIII) (P<0.05) in a concentration-dependent manner. The inhibition of Na(+)/K(+) ATPase activity was completely reversed by dithiothreitol (DTT); indicating reaction of these organochalcogens with thiol groups of the enzyme. The thiol oxidase activity of the compounds II and XIII was supported by the fact that the rate of DTT oxidation was increased significantly by both chalcogens. In the higher concentrations, the compounds (II) and (XIII) were strongly genotoxic and cytotoxic to human leukocytes cells, as verified by the DNA damage and cell viability evaluation. Our results suggest that at relatively high concentration organochalcogenides exhibit hemolytic and genotoxic action in human blood cells, which are probably linked to their thiol oxidase activity and preferential interaction with sulfhydryl groups critical to enzymes.
Assuntos
Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Compostos Organosselênicos/toxicidade , Telúrio/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eritrócitos/metabolismo , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Testes de Mutagenicidade , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/química , Fragilidade Osmótica/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Telúrio/administração & dosagem , Telúrio/químicaRESUMO
Neuronal malfunction is a characteristic feature of diabetic mellitus. Hence, the present study therefore sought to evaluate the effect of diphenyl diselenide (DPDS) on the antioxidant status, sodium pump, cholinergic and glutamatergic system in the rat brain of streptozotocin (STZ) induced diabetes. The results show that although STZ evoke a significant diminution on the antioxidant status and activity of Na(+)/K(+)-ATPase, the activity of acetylcholinesterase and glutamate uptake and release was not altered. However, DPDS was able to markedly restore the observed imbalance in cerebral antioxidant status and also relieve the inhibition of Na(+)/K(+)-ATPase caused by streptozotocin. Hence, we conclude that DPDS is a potential candidate in the management of neuronal dysfunction that often accompanied complications associated with diabetic hyperglycemia.
Assuntos
Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Córtex Cerebral/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Compostos Organosselênicos/farmacologia , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Ácido Ascórbico/análise , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Ácido Glutâmico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Glutationa/análise , Glutationa/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Estreptozocina/toxicidade , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
Studies on the interaction of dicholesteroyl diselenide (DCDS) and diphenyl diselenide (DPDS) with hepatic delta-aminolevulinic acid dehydratase (ALA-D) and different isoforms of lactate dehydrogenase (LDH) from different tissues were investigated. In addition, their antioxidant effects were tested in vitro by measuring the ability of the compounds to inhibit the formation of hepatic thiobarbituric acid reactive species (TBARS) induced by both iron (II) and sodium nitroprusside (SNP). The results show that while DPDS markedly inhibited the formation of TBARS induced by both iron (II) and SNP, DCDS did not. Also, the activities of hepatic delta-aminolevulinic acid dehydratase (ALA-D) and different isoforms of lactate dehydrogenase (LDH) were significantly inhibited by both DPDS and DCDS. Moreover, we further observed that the in vitro inhibition of different isoforms of lactate dehydrogenase by DCDS and DPDS likely involves the modification of the groups at the NAD+ binding site of the enzyme. Since organoselenides interacts with thiol groups on proteins, we conclude that the inhibition of different isoforms of lactate dehydrogenase by DPDS and DCDS possibly involves the modification of the thiol groups at the NAD+ binding site of the enzyme.
Assuntos
Antioxidantes/toxicidade , Derivados de Benzeno/toxicidade , Colesterol/análogos & derivados , Inibidores Enzimáticos/toxicidade , L-Lactato Desidrogenase/antagonistas & inibidores , Fígado/efeitos dos fármacos , Compostos Organosselênicos/toxicidade , Sintase do Porfobilinogênio/antagonistas & inibidores , Animais , Colesterol/toxicidade , Relação Dose-Resposta a Droga , Interações Medicamentosas , Coração/efeitos dos fármacos , Isoenzimas , L-Lactato Desidrogenase/metabolismo , Fígado/enzimologia , Masculino , Miocárdio/enzimologia , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sintase do Porfobilinogênio/metabolismo , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Male albino rats with diabetes induced by the administration of streptozotocin (STZ) (45 mg/kg, i.v.) were treated with oral administration of diphenyl diselenide (DPDS) pre-dissolved in soya bean oil. A significant reduction in blood glucose levels was observed in STZ-induced diabetic rats treated with DPDS compared with an untreated STZ diabetic group. The pharmacological effect of DPDS was accompanied by a marked reduction in the level of glycated proteins, and restoration of the observed decreased levels of vitamin C and reduced glutathione (GSH; in liver and kidney tissues) of STZ-treated rats. DPDS also caused a marked reduction in the high levels of thiobarbituric acid reactive substances (TBARS) observed in STZ-induced diabetic group. Finally, the inhibition of catalase, delta aminolevulinic acid dehydratase (eth-ALA-D) and isoforms of lactate dehydrogenase (LDH) accompanied by hyperglycemia were prevented by DPDS in all tissues examined. Hence, in comparison with our earlier report, the present findings suggests that, irrespective of the route of administration and the delivery vehicle, DPDS can be considered as an anti-diabetic agent due to its anti-hyperglycemic and antioxidant properties.
Assuntos
Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , L-Lactato Desidrogenase/metabolismo , Compostos Organosselênicos/farmacologia , Sintase do Porfobilinogênio/metabolismo , Administração Oral , Animais , Antioxidantes/administração & dosagem , Ácido Ascórbico/metabolismo , Derivados de Benzeno/administração & dosagem , Glicemia/análise , Catalase/metabolismo , Diabetes Mellitus Experimental/sangue , Glutationa/metabolismo , Hipoglicemiantes/administração & dosagem , Isoenzimas/metabolismo , Masculino , Compostos Organosselênicos/administração & dosagem , Estresse Oxidativo , RatosRESUMO
The aim of this study was to assess the effects of the organoselenium compound, 3'3-ditrifluormethyldiphenyl diselenide [(F(3)CPhSe)(2)], during the intra-uterine development of Wistar rats. Dams were given repeated doses of 1, 5 or 10mg/kg (F(3)CPhSe)(2) by intragastric route on gestation days 6-15, and cesarean sections were performed on day 20 of pregnancy. The numbers of implantation sites, living and dead fetuses and resorptions were recorded. Fetuses were weighed and stained with Alizarin red S for skeletal evaluation. The placental morphology was also evaluated. In 1mg/kg (F(3)CPhSe)(2) group, neither maternal toxicity nor prenatal growth retardation was observed. Conversely, in 5 and 10mg/kg groups, there was a decrease in maternal weight gain during pregnancy indicating that (F(3)CPhSe)(2) was maternally toxic, without affecting fetuses weight and length. (F(3)CPhSe)(2) caused some morphological alterations in placenta of 5 and 10mg/kg-exposed dams. Results also showed that skeletal variations were produced by (F(3)CPhSe)(2) only at doses (10mg/kg) in which a marked embryolethality was found. We conclude that (F(3)CPhSe)(2) was toxic to the dams and induced embryofeto-toxicity at doses equal to 10mg/kg.
Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Compostos Organosselênicos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/embriologia , Osso e Ossos/patologia , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Feto/patologia , Espectroscopia de Ressonância Magnética , Masculino , Tamanho do Órgão/efeitos dos fármacos , Placenta/patologia , Gravidez , Ratos , Reprodução/efeitos dos fármacos , Útero/patologiaRESUMO
The aim of the present study was to evaluate if diphenyl diselenide administered by oral route was effective in restoring gastric lesions induced by ethanol. The possible involvement of oxidative stress in diphenyl diselenide antiulcer effect was also evaluated. Different doses of diphenyl diselenide (dissolved in soya bean oil, 1mL/kg) were administered orally 1h before (pre-treatment study) or 1h after ethanol (70%, v/v, 2mL/kg, post-treatment study). Ulcer lesions were quantified 1h after ethanol administration (pre-treatment protocol) or 1h after diphenyl diselenide study (post-treatment protocol). Diphenyl diselenide (0.1-10mg/kg or 0.32-32micromol/kg), when administered previously or posteriorly prevented and reversed respectively, the development of gastric lesions induced by ethanol in rats. A number of markers of oxidative stress were examined in rat stomach including thiobarbituric acid reactive species (TBARS), catalase (CAT), superoxide dismutase (SOD), non-protein thiol groups (NPSH) and ascorbic acid. In addition to attenuating the gastric lesions, low doses of diphenyl diselenide prevented (pre-treatment) or reversed (post-treatment) the ethanol-induced changes in TBARS, SOD activity and ascorbic acid content. In conclusion, the present data reveal that diphenyl diselenide, administered by oral route, possesses an antiulcer effect by modulating antioxidant mechanisms.
Assuntos
Antiulcerosos , Derivados de Benzeno/farmacologia , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Úlcera Gástrica/tratamento farmacológico , Animais , Ácido Ascórbico/metabolismo , Catalase/metabolismo , Etanol , Mucosa Intestinal/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
This study was designed to determine whether the treatment with haloperidol (HP), valerian or both in association impairs the liver or kidney functions. Valerian alone did not affect oxidative stress parameters in the liver or kidney of rats. HP alone only increased glutathione (GSH) depletion in liver, but not in kidney. However, when HP was associated with valerian, an increase in lipid peroxidation levels and dichlorofluorescein (DCFH) reactive species production was observed in the hepatic tissue. Superoxide dismutase (SOD) and Catalase (CAT) activities were not affected by the HP plus valerian treatment in the liver and kidney of rats. HP and valerian when administered independently did not affect the activity of hepatic and renal delta-aminolevulinate dehydratase (delta-ALA-D), however, these drugs administered concomitantly provoked an inhibition of hepatic delta-ALA-D activity. The delta-ALA-D reactivation index was higher in rats treated with HP plus valerian than other treated groups. These results strengthen the view that delta-ALA-D can be considered a marker for oxidative stress. Serum aspartate aminotransferase (AST) activity was not altered by any treatment. However, serum alanine aminotransferase (ALT) activity was higher in the HP group and HP plus valerian group. Our findings suggest adverse interactions between haloperidol and valerian.
Assuntos
Haloperidol/efeitos adversos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Valeriana/efeitos adversos , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Catalase/sangue , Catalase/metabolismo , Interações Medicamentosas , Glutationa/sangue , Glutationa/metabolismo , Glutationa Peroxidase/sangue , Glutationa Peroxidase/metabolismo , Haloperidol/uso terapêutico , Rim/enzimologia , Rim/metabolismo , Rim/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/fisiologia , Masculino , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Sintase do Porfobilinogênio/antagonistas & inibidores , Sintase do Porfobilinogênio/sangue , Sintase do Porfobilinogênio/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Superóxido Dismutase/sangue , Superóxido Dismutase/metabolismoRESUMO
The aim of the present study was to evaluate pharmacological and toxicological properties of (Z)-2-(methylthio)-1-(butyltelluro)-1-phenylethene 1a, (Z)-1-(4-methylphenylsulfonyl)-2-(phenyltelluro)-2-phenylethene 1b, (Z)-2-(butyltelluro)-1-(benzylthio)-1-heptene 1c and (Z)-2-(phenylthio)-1-(butyltelluro)-1-phenylethene 1d. In vitro, vinylic telluride derivatives 1a, 1d and 1c were more effective in reducing lipid peroxidation than compound 1b. The maximal inhibitory effect of vinylic telluride derivatives on lipid peroxidation was in the following order: 1a = 1d > 1c > 1b. Compound 1b was more potent in inhibiting delta-ALA-D activity (delta-aminolevulinate dehydratase) than compounds 1c and 1d. Based on the in vitro properties presented by compounds 1a (an antioxidant) and 1b (a pro-oxidant), toxicological parameters were assessed in vivo and ex vivo in rats. Calculated LD50 of compounds 1a and 1b, administered by oral route, were 20.5 and 1.44 micromol kg(-1), respectively. Compound 1b induced behavioral alterations in the open field test. Renal and spleenic delta-ALA-D activities were inhibited in rats treated orally with compound 1a. Compound 1b stimulated delta-ALA-D activity in liver and spleen of rats. Rats treated with compound 1b had increased hepatic, renal and spleenic lipid peroxidation. Renal and hepatic markers were not altered when compounds 1a and 1b were administered to rats at doses of around LD50, while compound 1a at high doses changed aspartate aminotransferase activity and urea levels. Based on in vitro results, this study demonstrated that compounds 1a and 1d are promising antioxidant compounds. Ex vivo data reinforce compound 1a as a promising drug for more detailed pharmacological studies.
Assuntos
Antioxidantes/toxicidade , Compostos Organometálicos/toxicidade , Telúrio/toxicidade , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/patologia , Dose Letal Mediana , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Tamanho do Órgão/efeitos dos fármacos , Sintase do Porfobilinogênio/metabolismo , Ratos , Ratos WistarRESUMO
The main objective of the present study was to compare the inhibitory effect of diphenyl diselenide (PhSe)(2) and Pb(2+) on mice and fruit fly delta-Aminolevulinate dehydratase (delta-ALA-D). Optimum pH was quite different for mice (pH 6.5) and flies (pH 8.5). At pH 8.5, the inhibitory potency of (PhSe)(2) was higher for the fruit flies (IC(50) 8.2 micromol/l) than for mice (IC(50) 19.5 micromol/l). Pb(2+) inhibited mice delta-ALA-D at pH 6.5 (IC(50) 6.2 micromol/l) and 8.5 (IC(50) 5.6 micromol/l) with higher potency than the fly enzyme (IC(50) 43.7 micromol/l). delta-ALA-D transcription was reduced by 15% in flies exposed to 0.3 mmol/kg (PhSe)(2), which is similar to the reduction observed in activity measured in the presence of dithiothreitol. The three-dimensional prediction by SWISS-PROT mouse and fly delta-ALA-D revealed differences in the number of hydrogen bonds and turns for the 2 enzymes. Sulfhydryl groups (-SH) that could be oxidized by (PhSe)(2) are conserved in the two sources of enzyme. Distinct responsiveness to pH, (PhSe)(2) and Pb(2+) of these enzymes may be related to subtle differences in tertiary or quaternary structure of mouse and fly delta-ALA-D. Furthermore, mechanism underlying enzyme inhibition after in vivo exposure seems to be different for Drosophila melanogaster and rodent enzymes.
Assuntos
Derivados de Benzeno/toxicidade , Drosophila melanogaster/enzimologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Compostos Organosselênicos/toxicidade , Sintase do Porfobilinogênio/genética , Transcrição Gênica/efeitos dos fármacos , Animais , Masculino , Camundongos , Sintase do Porfobilinogênio/antagonistas & inibidoresRESUMO
Oxidative stress is implicated in the pathogenesis of diabetes mellitus. Selenium supplementation has some benefits in experimental models of diabetes mellitus. This study evaluated whether dietary diphenyl diselenide, a simple synthetic organoselenium compound with antioxidant properties, reduces the streptozotocin (STZ)-induced toxicity. STZ-induced diabetic rats were fed with either standard and diphenyl diselenide (10 ppm) supplemented diets. In experimental trials, dietary diphenyl diselenide significantly decreased mortality rate (p<0.05) induced by STZ treatment. No correlation between this effect and glycemic levels were found. Diphenyl diselenide intake also promoted an increase in vitamin C, -SH levels (liver, kidney and blood) and in catalase (liver and kidney) activity, which were decreased in STZ-treated rats. In enzyme assays, diphenyl diselenide supplementation caused a significant improvement in platelets NTPDase and 5'-nucleotidase activities in STZ-induced diabetic rats when compared to the control and diabetic groups (p<0.05). Nevertheless, this supplementation did not modify the inhibition induced by STZ in delta-ALA-D activity. Our findings suggest that diphenyl diselenide compound showed beneficial effects against the development of diabetes by exhibiting antioxidant properties.
Assuntos
Derivados de Benzeno/farmacologia , Diabetes Mellitus Experimental/prevenção & controle , Compostos Organosselênicos/farmacologia , 5'-Nucleotidase/metabolismo , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Diabetes Mellitus Experimental/metabolismo , Dieta , Masculino , Tamanho do Órgão/efeitos dos fármacos , Sintase do Porfobilinogênio/metabolismo , Ratos , Ratos Wistar , Selênio/análise , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Sulfidrila/metabolismoRESUMO
In the present study, we investigated if thiol-reducing agents are capable of altering mercury (Hg2+), lead (Pb2+) and cadmium (Cd2+) effects on platelet glutamatergic system. Dimercaprol (BAL), a dithiol chelating agent therapeutically used for the treatment of heavy metals poisoning, was capable of protecting the [3H]-glutamate binding against the effects caused by Pb2+ and Hg2+. 2,3-Dimercaptopropane-1-sulfonic acid (DMPS), another dithiol-reducing chelating agent, was capable of protecting the effect caused by Cd2+, Pb2+ and Hg2+. The similar effect was observed with addition of dithiothreitol (DTT) on [3H]-glutamate binding in human platelets. Dithiol-reducing agents (BAL, DMPS and DTT) alone did not alter [3H]-glutamate binding. In contrast, reduced glutathione (GSH), a monothiol-reducing agent, caused a significant inhibition on [3H]-glutamate binding at all concentrations tested. GSH did not modify heavy metal effects on [3H]-glutamate binding in platelets. The findings of the present investigation indicate that dithiol-reducing agents are capable of altering Hg2+, Pb2+ and Cd2+ effects on platelet glutamatergic system. In vitro data on chelating-metal interactions provide only an estimated guide to the treatment of heavy metal poisoning. Consequently, more studies in intoxicated patients are necessary to determine the precise use of the peripheral models and chelating agents.