RESUMO
Redox imbalance leads to oxidative stress that causes irreversible cellular damage. The incorporation of the antioxidant element selenium (Se) in the structure of pyridinium salts has been used as a strategy in chemical synthesis and can be useful in drug development. We investigated the antioxidant activity of Se-containing pyridinium salts (named Compounds 3A, 3B, and 3C) through in vitro tests. We focused our study on liver protein carbonylation, liver lipoperoxidation, free radical scavenging activity (1,1-diphenyl-2-picryl-hydrazil [DPPH]; 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid [ABTS]), and enzyme-mimetic activity assays (glutathione S-transferase [GST]-like; superoxide dismutase [SOD]-like). In addition, 2-(4-chlorophenyl)-2-oxoethyl)-2-((phenylselanyl)methyl)pyridin-1-ium bromide (3C) was selected to evaluate the acute oral toxicity in mice due to the best antioxidant profile. The three compounds were effective in reducing the levels of protein carbonylation and lipoperoxidation in the liver in a µM concentration range. All compounds demonstrated scavenger activity of DPPH and ABTS radicals, and GST-like action. No significant effects were detected in the SOD-like assay. Experimental data also showed that the acute oral treatment of mice with Compound 3C (50 and 300 mg/kg) did not cause mortality or change markers of liver and kidney functions. In summary, our findings reveal the antioxidant potential of Se-containing pyridinium salts in liver tissue, which could be related to their radical scavenging ability and mimetic action on the GST enzyme. They also demonstrate a low toxicity potential for Compound 3C. Together, the promising results open space for future studies on the therapeutic application of these molecules.
Assuntos
Benzotiazóis , Compostos de Bifenilo , Hepatopatias , Selênio , Ácidos Sulfônicos , Camundongos , Animais , Antioxidantes/metabolismo , Selênio/farmacologia , Sais/farmacologia , Sais/metabolismo , Estresse Oxidativo , Hepatopatias/metabolismo , Superóxido Dismutase/metabolismo , Fígado/metabolismo , Preparações Farmacêuticas/metabolismoRESUMO
This work presents the design, synthesis, and MAO-B inhibitor activity of a series of chalcogenyl-2,3-dihydrobenzofurans derivatives. Using solvent- and metal-free methodology, a series of chalcogen-containing dihydrobenzofurans 7-9 was obtained with yields ranging from 40% to 99%, using an I2 /DMSO catalytic system. All compounds were fully structurally characterized using 1 H and 13 C NMR analysis, and the unprecedented compounds were additionally analyzed using high-resolution mass spectrometry (HRMS). In addition, the mechanistic proposal that iodide is the most likely species to act in the transfer of protons along the reaction path was studied through theoretical calculations. Finally, the compounds 7b-e, 8a-e, and 9a showed great promise as inhibitors against MAO-B activity.
RESUMO
RATIONALE: Obesity is considered one of the major global health problems and increases the risk of several medical complications, such as diabetes and mental illnesses. OBJECTIVE: The present study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) on obesity parameters, behavioral and neurochemical alterations in hypothalamic obese rats. METHODS: Male Wistar rats received subcutaneous neonatal injections of monosodium glutamate (MSG, 4g/kg) or saline. After the Lee Index evaluation, rats were divided into groups and treated with 4-PSQ (5 mg/kg, intragastric route) or canola oil once a day (post-natal days (PND) 60â76). Open-field, elevated plus-maze, forced swim task, object recognition/location memory, and stepdown inhibitory avoidance tasks were conducted from PND 66 to 74. On PND 76, rats were euthanized and epididymal fat, blood, cerebral cortex, andhippocampus were removed. Blood biochemical parameters and cortical/hippocampal acetylcholinesterase (AChE) and Na /K -ATPase activities were assessed. RESULTS: MSG increased the Lee Index characterizing the chemically induced hypothalamic obesity model. 4-PSQ reversed the increases of epididymal fat, blood glucose, and triglyceride levels caused by MSG exposure. 4-PSQ attenuated anxiety-like and depression-like behaviors induced by neonatal administrations of MSG. Memory deficits found in MSG-obese rats were reversed by treatment with 4-PSQ. Neurochemical alterations produced by MSG evidenced by stimulation ofNa+/K+-ATPase and AChE activities in the cerebral cortex and hippocampus of rats were normalized by 4-PSQ treatment. CONCLUSIONS: In brief, 4-PSQ therapy improved hypothalamic obesity-related parameters, as well as psychiatric symptoms, cognitive impairment, and neurochemical alterations found in obese rats.
Assuntos
Hipotálamo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/psicologia , Quinolinas/administração & dosagem , Selênio/administração & dosagem , Animais , Hipotálamo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Obesidade/induzido quimicamente , Obesidade/metabolismo , Ratos , Ratos Wistar , Glutamato de Sódio/toxicidadeRESUMO
We describe herein a new approach to prepare unprecedented bioactive indolizine motifs decorated with organosulfur and organoselenium groups. A total of 12 1-sulfanylindolizines and 2 1-selanylindolizines were prepared in excellent yields by an intramolecular annulation of easily prepared chalcogen-containing pyridinium salts. The reaction is fast (1 h at 70 °C or 5 min under sonication) and transition-metal-free, using glycerol as a green solvent.
RESUMO
Determining precisely the postmortem interval (PMI) is a key parameter for forensic researches, given that various physical, biochemical and metabolic changes begin to occur in the body after death. In the present study, the Na+/K+-ATPase, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated. For this, male adult Swiss mice were killed by isoflurane inhalation anesthesia and divided into four groups according to time of death (0, 6, 24 and 48â¯h). The brain, liver, kidney and skeletal muscle tissues were removed. Our results revealed that at the time of 6â¯h, there was a decrease on Na+/K+-ATPase and GST activities in the brain and liver tissues, respectively. In addition, at this time point, an increase on renal GST activity was verified. At the time of 24â¯h, an increase on the cerebral AChE and renal GST activities was observed, while the cerebral Na+/K+-ATPase activity was decreased. Forty-eight hours after death, cerebral Na+/K+-ATPase and renal GST activities remained decreased and increased, respectively. In addition, no alteration was observed on the GST activity in the skeletal muscle and brain (in PMIs evaluated). The present study revealed that the brain and kidney (at the times of 24 and 48â¯h) were the tissues that suffered the most changes in almost all the enzymes evaluated. Our results demonstrated that enzyme activity assessments are reliable, easy-to-perform and low-cost determinations, and could be promising postmortem markers.
Assuntos
Acetilcolinesterase/metabolismo , Biomarcadores/metabolismo , Encéfalo/enzimologia , Medicina Legal/métodos , Glutationa Transferase/metabolismo , Rim/enzimologia , Fígado/enzimologia , Músculo Esquelético/enzimologia , Mudanças Depois da Morte , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Masculino , Camundongos , Fatores de Tempo , Distribuição TecidualRESUMO
Behavioral studies have suggested that (p-ClPhSe)2 elicits an anorectic-like action in rats by inducing multiple effects such as satiety-enhancing effect, malaise and specific flavor; however, the molecular mechanisms underlying its anorexigenic action remain unclarified. Here, male Sprague-Dawley rats received acute and sub-chronic intraperitoneal treatments with (p-ClPhSe)2; thereafter, in vivo and ex vivo analyses were carried out. The present study reveals that the reduction of food intake resulting from a single treatment with (p-ClPhSe)2 (1mg/kg, i.p.) was associated with decreased hypothalamic levels of pro-melanin-concentrating hormone (pro-MCH) and orexin precursor. In addition, repeated administrations of (p-ClPhSe)2 (10mg/kg; i.p.) for 7 days induced sustained food intake suppression, body weight loss and white fat reduction. Measurements of brown adipose tissue content and temperature as well as data obtained from a pair-fed group indicated that the effects of (p-ClPhSe)2 on the body weight are closely related to its anorexigenic actions, ruling out the possibility of increased thermogenesis. Furthermore, (p-ClPhSe)2 reduced the hypothalamic orexin precursor levels when repeatedly administered to rats. Sub-chronic treatment with (p-ClPhSe)2 caused a decrease of serum triglyceride levels and down-regulation of hepatic cholesterol content. Therefore, the current study characterized the anorectic and reducing body weight actions of (p-ClPhSe)2 in Sprague-Dawley rats. Besides, the set of results suggests that food intake suppressant effects triggered after (p-ClPhSe)2 administration to rats are mainly related with the lower orexin levels in hypothalamus after acute and sub-chronic treatments.
Assuntos
Anorexia/induzido quimicamente , Anorexia/patologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Compostos Organosselênicos/efeitos adversos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Anorexia/sangue , Anorexia/psicologia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Resposta de Saciedade/efeitos dos fármacos , Fatores de Tempo , Triglicerídeos/sangueRESUMO
The aim of the present study was to investigate the effects of SCH58261, a selective adenosine A2A receptor antagonist, on striatal toxicity induced by 3-nitropropionic acid (3-NP) in rats. The experimental protocol consisted of 10 administrations (once a day) of SCH58261 (0.01 or 0.05 mg/kg/day, intraperitoneal, i.p.). From 7th to 10th day, 3-NP (20 mg/kg/day, i.p.) was injected 1 h after SCH58261 administration. Twenty-four hours after the last 3-NP injection, the body weight gain, locomotor activity (open-field test), motor coordination (rotarod test), striatal succinate dehydrogenase (SDH) activity and parameters linked to striatal oxidative status were evaluated in rats. The marked body weight loss resulting from 3-NP injections in rats was partially protected by SCH 58261 at both doses. SCH 58261 at the highest dose was effective against impairments on motor coordination and locomotor activity induced by 3-NP. SCH 58261 was unable to restore the inhibition of SDH activity caused by 3-NP. In addition, the increase in striatal reactive species (RS) levels, depletion of reduced glutathione (GSH) content and stimulation of glutathione reductase (GR) activity provoked by 3-NP injections were alleviated by both doses of SCH 58261. The highest dose of SCH 58261 was also effective in attenuating the increase of protein carbonyl levels as well as the inhibition of glutathione peroxidase (GPx) activity in rats exposed to 3-NP. Our results revealed that reduction of oxidative stress in rat striatum by adenosine A2A receptor antagonism contributes for alleviating 3-NP-induced toxicity.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Corpo Estriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nitrocompostos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propionatos/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Animais , Corpo Estriado/metabolismo , Glutationa/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Teste de Desempenho do Rota-RodRESUMO
The aim of this study was to investigate whether (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) protects against hepatotoxicity induced by thioacetamide (TAA). On the first day of treatment, male adult Wistar rats received BPD (10 or 50 mg·kg-1). On the second day, the rats received a single intraperitoneal injection of TAA (400 mg·kg-1). Twenty-four hours after TAA administration, biochemical determinations and liver histological analysis were carried out. BPD (50 mg·kg-1) reduced plasma aspartate and alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities increased by TAA exposure. Treatment with BPD was effective against increased lipid peroxidation levels and attenuated a decrease in hepatic reduced glutathione and ascorbic acid levels as well as an inhibition of glutathione peroxidase activity caused by TAA exposure. The higher dose of BPD protected against the inhibition of hepatic δ-aminolevulinic dehydratase activity induced by TAA. Finally, histopathological examination of the liver showed that BPD markedly ameliorated TAA-induced hepatic injury. In conclusion, BPD protected against hepatotoxicity and oxidative stress caused by TAA exposure in rats.
Assuntos
Fígado/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Tioacetamida/toxicidade , Animais , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Preliminary findings suggest that food intake reduction induced by p-chloro-diphenyl diselenide [(p-ClPhSe)2] in rats is mediated by a satiating action; however, additional experiments are necessary to clarify its actions. The purpose of this study was to investigate the effects of diets supplemented with (p-ClPhSe)2 on feeding behavior of rats as well as the (p-ClPhSe)2 effectiveness in producing aversive reactions or specific flavor. The results demonstrated that behavioral satiety sequence (BSS) was preserved in animals exposed to (p-ClPhSe)2-supplemented diets (0.01 and 0.1%) and associated with a shift of the onset of resting to the left indicating a satiating action at the first contact. In addition, the frequency, the mean duration and the mean size of meals were decreased in rats exposed to a 0.1% (p-ClPhSe)2 diet. Alternatively, a second contact with a 0.01% (p-ClPhSe)2 diet caused disruption of BSS and pronounced changes in the meal pattern, suggesting that it produces aversiveness. In fact, rats developed a significant taste aversion to the saccharin solution after receiving the administration of (p-ClPhSe)2 (1 and 10mg/kg; i.p.). Lastly, a diet containing 0.1% of (p-ClPhSe)2 seems to alter the palatability of food given that rats had a preference for the control diet. The findings of the present study suggest that (p-ClPhSe)2 reduced the food intake of rats by inducing a satiating action at the first contact, but it also produced aversive reactions when rats were re-exposed to it. A specific flavor seems also to contribute to (p-ClPhSe)2 suppressant effects on feeding.
Assuntos
Dieta , Suplementos Nutricionais , Comportamento Alimentar , Compostos Organosselênicos/administração & dosagem , Tecido Adiposo , Animais , Aprendizagem da Esquiva , Peso Corporal , Comportamento de Escolha , Condicionamento Psicológico , Comportamento Alimentar/fisiologia , Masculino , Atividade Motora , Ratos Wistar , Saciação/fisiologia , Percepção Gustatória , Fatores de TempoRESUMO
Monosodium glutamate (MSG) is a neuroexcitatory amino acid commonly used as flavoring of foods. MSG neonatal administration to animals leads to behavioral and physiological disorders in adulthood, including increased pain sensitivity. This study aimed to investigate the effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, on nociception induced by MSG. Newborn Wistar rats received 10 subcutaneous injections of MSG at a dose of 4.0g/kg or saline (once daily). At the 60th day of life, the rats were daily treated with (PhSe)2 (1mg/kg) or vehicle (canola oil) by the intragastric route for 7 days. The behavioral tests (locomotor activity, hot plate, tail-immersion and mechanical allodynia) were carried out. Ex vivo assays were performed in samples of hippocampus to determine Na(+), K(+)-ATPase and Ca(2+)-ATPase activities, cytokine levels and [(3)H]glutamate uptake. The results demonstrated that MSG increased nociception in the hot plate test and in the mechanical allodynia stimulated by Von-Frey hair but did not alter the tail immersion test. (PhSe)2 reversed all nociceptive behaviors altered by MSG. MSG caused an increase in Na(+),K(+)-ATPase and Ca(2+)-ATPase activities and in pro-inflammatory cytokine levels and a decrease in the anti-inflammatory cytokine and in the [(3)H]glutamate uptake. (PhSe)2 was effective in reversing all alterations caused by MSG. The results indicate that (PhSe)2 had a potential antinociceptive and anti-inflammatory action in the MSG model.
Assuntos
Analgésicos/uso terapêutico , Derivados de Benzeno/uso terapêutico , Compostos Organosselênicos/uso terapêutico , Medição da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Glutamato de Sódio/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Animais Recém-Nascidos , Derivados de Benzeno/farmacologia , ATPases Transportadoras de Cálcio/metabolismo , Citocinas/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Atividade Motora/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Dor/induzido quimicamente , Ratos , Glutamato de Sódio/efeitos adversos , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
RATIONALE: The searching for safe and effective antiobesity drugs has been the subject of intense research. Previous studies have shown several pharmacological applications of organoselenium compounds; however, their possible anorectic-like actions have not been investigated. OBJECTIVE: This study aims to investigate the effects of (PhSe)2 and (p-ClPhSe)2 on feeding behavior of rats and their potential as weight-reducing agents. METHODS: The effects of intraperitoneal administration of diselenides were investigated through the microstructural pattern of feeding behavior, behavioral satiety sequence (BSS), hypothalamic serotonin (5-HT) uptake, body weight, and epididymal fat content of male rats. RESULTS: Our findings demonstrated that food intake of fasted rats was reduced by both diselenides (1 and 10 mg/kg). Diphenyl diselenide [(PhSe)2] (1 mg/kg) and p-chloro-diphenyl diselenide [(p-ClPhSe)2] (10 mg/kg) decreased the frequency, mean duration, and mean size of meals compared with the control treatment. The BSS structure was preserved when organoselenium compounds (1 mg/kg) were administered, and it was associated to a displacement to the left when the resting period started indicating a satiating action. Inhibition of 5-HT uptake in the hypothalamus (â¼20 %) was also found in rats treated with low doses of (PhSe)2 and (p-ClPhSe)2 (1 mg/kg). Treatments with a high dose of both diselenides (10 mg/kg) carried out for 7 days induced weight loss and epididymal fat reduction in sated rats. CONCLUSION: This study suggests that diselenides caused a satiating action in rats that could be partially explained by the inhibition of hypothalamic 5-HT uptake. These organoselenium compounds were potential weight-reducing agents when repeatedly administered.
Assuntos
Derivados de Benzeno/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Resposta de Saciedade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Comportamento Alimentar/fisiologia , Masculino , Ratos , Ratos Wistar , Resposta de Saciedade/fisiologiaRESUMO
The protective effect of ebselen was investigated against 3-nitropropionic acid (3-NP)-induced behavioral and biochemical toxicities in rats. Ebselen (10 or 25 mg/kg, intragastrically) was administered to rats 30 min before 3-NP (20 mg/kg, intraperitoneally) once a day for a period of 4 days. Locomotor activity, motor coordination, and body weight gain were determined. The striatal content of reactive oxygen species (ROS), reduced glutathione (GSH), ascorbic acid (AA), and protein carbonyl as well as catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) activities was determined 24 h after the last dose of 3-NP. Na(+)/ K(+)-ATPase, succinate dehydrogenase (SDH), and δ-aminolevulinic dehydratase (δ-ALA-D) activities were also determined. The results demonstrated that ebselen at a dose of 25 mg/kg, but not at 10 mg/kg, protected against (1) a decrease in locomotor activity, motor coordination impairment, and body weight loss; (2) striatal oxidative damage, which was characterized by an increase in ROS levels, protein carbonyl content, and GR activity, an inhibition of CAT and GPx activities, and a decrease in GSH levels; and (3) an inhibition of SDH and Na(+)/K(+)-ATPase activities, induced by 3-NP. GST activity and AA levels were not modified by ebselen or 3-NP. Ebselen was not effective against the inhibition of δ-ALA-D activity induced by 3-NP. The results revealed a significant correlation between SDH activity and ROS levels, and SDH activity and latency to fall (rotarod test). The present study highlighted the protective effect of ebselen against 3-NP-induced toxicity in rats.
Assuntos
Azóis/farmacologia , Nitrocompostos/toxicidade , Compostos Organosselênicos/farmacologia , Propionatos/toxicidade , Succinato Desidrogenase/metabolismo , Animais , Azóis/química , Comportamento Animal/efeitos dos fármacos , Isoindóis , Masculino , Compostos Organosselênicos/química , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de OxigênioRESUMO
UNLABELLED: Monosodium glutamate (MSG) has been the target of research due to its toxicological effects. AIMS: We investigated the depressive- and anxiogenic-like behaviors in rats exposed to neonatal subcutaneous injection of MSG. The involvement of the serotonergic system, by measuring [(3)H] serotonin (5-HT) uptake in cerebral cortices, and the hypothalamic pituitary adrenal (HPA) axis, by determining serum adrenocorticotropic hormone (ACTH) and corticosterone levels, was also examined. MATERIALS AND METHODS: Male and female newborn Wistar rats were divided into control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 5th postnatal day. The behavioral tests [spontaneous locomotor activity, contextual fear conditioning, and forced swimming test (FST)] were performed from the 60th to 64th postnatal day. MSG-treated animals showed alteration in the spontaneous locomotor activity, an increase in the number of fecal pellets and the number of animal's vocalizations and urine occurrence, and a decrease in the grooming time. KEY FINDINGS: The MSG exposure increased the immobility time in the FST and the freezing reaction in the contextual fear conditioning. Additionally, MSG treatment increased the [(3)H]5-HT uptake in the cerebral cortices of rats and induced a deregulation of HPA axis function (by increasing serum ACTH and corticosterone levels). SIGNIFICANCE: In conclusion MSG-treated rats are more susceptible to develop anxiogenic- and depressive-like behaviors, which could be related to a dysfunction in the serotonergic system.
Assuntos
Transtornos de Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Transtorno Depressivo/induzido quimicamente , Aromatizantes/toxicidade , Glutamato de Sódio/toxicidade , Hormônio Adrenocorticotrópico/metabolismo , Animais , Animais Recém-Nascidos , Transtornos de Ansiedade/metabolismo , Córtex Cerebral/efeitos dos fármacos , Corticosterona/metabolismo , Transtorno Depressivo/metabolismo , Medo/efeitos dos fármacos , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Injeções Subcutâneas , Locomoção/efeitos dos fármacos , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Radioimunoensaio , Ratos , Ratos Wistar , Serotonina/metabolismo , Natação/fisiologiaRESUMO
OBJECTIVES: The excitotoxin 3-nitropropionic acid (3-NP) induces a suitable experimental model of Huntington's disease (HD). This compound induces neurodegeneration via glutamatergic activation and oxidative stress, suggesting that the metabotropic glutamate receptor blockage and free radical scavenging are potential therapeutic targets in HD. In this study, we evaluated the role of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP), a selective mGlu5 receptor antagonist, in a 3-NP model of HD. METHODS: We administered 3-NP (20 mg/kg, intraperitoneal) to rats for 4 days. MTEP at doses of 2·5 and 5 mg/kg was administered 30 min before 3-NP. Behavioral tests and biochemical experiments were performed to assess the effects of 3-NP and the ability of MTEP to ameliorate these changes. RESULTS: 3-NP administration induced body weight loss, decreased locomotor activity, and inhibition of succinate dehydrogenase and Na(+)-K(+) adenosine triphosphate (ATP)ase activities in rat striatum. We also observed increases in reactive species (RS) levels and glutathione reductase activity, decreased non-protein thiol levels, and an inhibition of glutathione peroxidase activity in the striatum of rats treated with 3-NP. Notably, all of these effects were attenuated by MTEP treatment. DISCUSSION: Our results demonstrate the neuroprotective effect of MTEP and reinforce the involvement of mGluR5 in 3-NP-induced oxidative stress in rat striatum.
Assuntos
Corpo Estriado/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piridinas/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Doença de Huntington/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Nitrocompostos , Estresse Oxidativo/fisiologia , Propionatos , Ratos Wistar , Receptor de Glutamato Metabotrópico 5/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Succinato Desidrogenase/metabolismo , Redução de Peso/efeitos dos fármacos , Redução de Peso/fisiologiaRESUMO
Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1)). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1) day(-1), per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Cisplatino/efeitos adversos , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Tiazolidinedionas/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Ácido Ascórbico/sangue , Catalase/metabolismo , Creatinina/sangue , Glutationa/sangue , Glutationa Peroxidase/metabolismo , Injeções Intraperitoneais , Rim/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Pioglitazona , Superóxido Dismutase/metabolismoRESUMO
The present study investigated the protective role of antioxidant (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD), an organoselenium compound, against the renal injury induced by cisplatin in rats. Canola oil or BPD (50 mg kg(-1)) was administered orally by gavage once a day for 6 days to rats. The first dose of BPD was given 24 h before a single intraperitoneal injection of saline or cisplatin (7 mg kg(-1)). At day 7, animals were killed and parameters related to renal injury were determined. The histological analysis showed that cisplatin caused renal injury in rats, which was accompanied by an increase in urea and creatinine levels in plasma. The increase of plasma creatinine levels negatively correlated with renal antioxidant defenses including ascorbic acid (AA) and reduced glutathione (GSH) content as well as glutathione S-transferase (GST), glutathione peroxidase (GPx) and catalase (CAT) activities. As revealed by histological analysis, BPD ameliorated tubular injury in rat kidney and reduced plasma markers altered by cisplatin. The administration of BPD to rats attenuated the reduction of renal AA and GSH content in animals exposed to cisplatin. The decrease of GST activity, but not GPx and CAT activities, in rats exposed to cisplatin was totally reversed by BPD administration. BPD was also effective in attenuating the inhibition of a sulfhydryl enzyme sensitive to oxidative stress, δ-aminolevulinic dehydratase, in kidneys of rats exposed to cisplatin. The present study demonstrated that BPD reduced renal injury induced by cisplatin in rats and this effect seems to be related to antioxidant mechanisms.
Assuntos
Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Rim/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Animais , Ácido Ascórbico/sangue , Catalase/metabolismo , Creatinina/sangue , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Injeções Intraperitoneais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
This study was designed to evaluate the effects of bis selenide on Huntington disease (HD)-like signs induced by 3-nitropropionic acid (3-NP) in rats. To this aim, rats were treated for 4 days with bis selenide (5 or 20 mg/kg/day, per oral) 30 min before 3-NP (20 mg/kg/day, intraperitoneally). The body weight gain, locomotor activity, motor coordination, and biochemical parameters in striatal preparations were assessed 24 h after the last injection of 3-NP. The highest dose of bis selenide was effective in protecting against body weight loss and motor coordination deficit induced by 3-NP. The impairment of locomotor activity caused by 3-NP was abolished by bis selenide at both doses. Bis selenide (5 and 20 mg/kg) partially restored succinate dehydrogenase activity inhibited after 3-NP exposure. The dose of 20 mg/kg of bis selenide recovered partially δ-aminolevulinic acid dehydratase activity, and totally Na(+), K(+)-ATPase activity, two sulfhydryl enzymes sensitive to oxidizing agents, which had their activities inhibited by 3-NP. Also, 3-NP led to an increase in protein carbonyl levels and glutathione reductase activity and inhibited catalase activity-alterations that were reversed by bis selenide administration at both doses. The highest dose of bis selenide was effective against the increase of RS levels, the depletion of reduced glutathione content, and the inhibition of glutathione peroxidase activity induced by 3-NP. Bis selenide was not effective against inhibition of SOD activity caused by 3-NP. These findings demonstrate that bis selenide elicited protective effects against HD-like signs induced by 3-NP in rats.
Assuntos
Ataxia/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Complexo II de Transporte de Elétrons/antagonistas & inibidores , Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/antagonistas & inibidores , Nitrocompostos/antagonistas & inibidores , Compostos Organosselênicos/uso terapêutico , Propionatos/antagonistas & inibidores , Animais , Ataxia/enzimologia , Corpo Estriado/enzimologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Estrutura Molecular , Proteínas do Tecido Nervoso/análise , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Nitrocompostos/toxicidade , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Propionatos/toxicidade , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Teste de Desempenho do Rota-Rod , Succinato Desidrogenase/antagonistas & inibidores , Aumento de Peso/efeitos dos fármacosRESUMO
The present study examined the effect of peroral administration of bis(phenylimidazoselenazolyl) diselenide (BPIS) in thermal and chemical models of pain in mice. The involvement of the opioid system in the BPIS antinociceptive effect was also examined, as well as potential nonspecific disturbances in locomotor activity or signs of acute toxicity. BPIS (25-100 mg/kg) induced an increase in tail-immersion response latency and this effect was significant at pretreatment times of 15 min to 4 h, but not at 8 h. The hot-plate response latency was also increased by the administration of BPIS (25-100 mg/kg). BPIS, at doses of 25 and 50 mg/kg, inhibited writhing behaviour caused by an intraperitoneal acetic acid injection. Both early and late phases of nociception caused by the intraperitoneal formalin injection were inhibited by BPIS (10-50 mg/kg). BPIS, administered at doses equal to or greater than 10 and 25 mg/kg, reduced nociception produced by an intraperitoneal injection of capsaicin and glutamate, respectively. The antinociceptive effect of BPIS, when assessed in the tail-immersion test, was not abolished by naloxone. BPIS (10-50 mg/kg) did not alter alanine transaminase and aspartate transaminase activities (parameters of hepatic function) or urea and creatinine levels (parameters of renal function), and did not affect motor activity in the open-field test. The results indicate that BPIS produced an antinociceptive action without causing motor disturbances or toxicity. Moreover, opioidergic mechanisms seem not to be involved in the antinociceptive action of BPIS. Here, BPIS has been found to be a novel organoselenium compound with antinociceptive properties; however, more studies are required to examine its therapeutic potential for pain treatment.
Assuntos
Dor Aguda/prevenção & controle , Analgésicos não Narcóticos/uso terapêutico , Neurônios/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Compostos Organosselênicos/uso terapêutico , Dor Aguda/sangue , Dor Aguda/fisiopatologia , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/efeitos adversos , Animais , Comportamento Animal , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ingestão de Energia/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Dor Nociceptiva/sangue , Dor Nociceptiva/fisiopatologia , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/efeitos adversos , Medição da Dor , Distribuição Aleatória , Testes de Toxicidade Aguda , Aumento de Peso/efeitos dos fármacosRESUMO
CONTEXT: Organoselenium compounds have been described as antioxidant and neuroprotective agents. OBJECTIVE: To evaluate the antioxidant action of 2,2'-dithienyl diselenide (DTDS) and its effects in brain monoamine oxidase (MAO) activity in vitro. MATERIALS AND METHODS: Assays for reactive species (RS), lipid peroxidation, protein oxidation, MAO A and B activities in rat brain homogenate as well as mimetic dehydroascorbate reductase and glutathione S-transferase activities were performed using DTDS (µM range). RESULTS: DTDS was effective in decreasing the levels of RS as well as lipid peroxidation induced by malonate, sodium nitroprusside or FeCl2/EDTA and protein carbonyl in the rat brain homogenate. DTDS elicited dehydroascorbate reductase-like and glutathione S-transferase-like activities. DTDS was effective in inhibiting both MAO-A and MAO-B activities. DISCUSSION: The results demonstrated that DTDS is an antioxidant agent with non-selective inhibitory effect on MAO activity. CONCLUSION: DTDS is a promising molecule to be evaluated in experimental models of neurological diseases.
Assuntos
Antioxidantes/farmacologia , Encéfalo/enzimologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Compostos Organosselênicos/farmacologia , Tiofenos/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Masculino , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
The present study was designed to investigate the effects of p-methoxyl-diphenyl diselenide (OMePhSe)(2) on oxidative stress and renal damage parameters of mice exposed to cisplatin. (OMePhSe)(2) (50 and 100 mg/kg/day) was orally administered to mice for six consecutive days. On the third day after the beginning of (OMePhSe)(2) treatment, the renal toxicity was induced by injecting cisplatin (10 mg/kg intraperitoneal) in mice. (OMePhSe)(2) treatment (50 mg/kg) partially reduced plasma urea and creatinine levels increased by cisplatin. Histopathological examination of kidneys showed that (OMePhSe)(2) ameliorated renal injury caused by cisplatin. (OMePhSe)(2) attenuated the decrease in reduced glutathione (GSH) and ascorbic acid (AA) levels, the inhibition of glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and catalase (CAT) activities caused by cisplatin in kidney. (OMePhSe)(2) treatment partially protected against the inhibition of renal δ-aminolevulinic dehydratase (δ-ALA-D) activity caused by cisplatin. No alteration in renal lipid peroxidation levels was found in cisplatin and/or (OMePhSe)(2) groups. (OMePhSe)(2) was effective against the increase in reactive species (RS) levels caused by the cisplatin exposure. Based on the renoprotective and antioxidant actions of (OMePhSe)(2) we suggest that this organoselenium compound could be considered a feasible candidate to protect against toxicity commonly encountered in cisplatin exposure.