RESUMO
The aim of this study was to investigate the ability of tannic acid (TA) in preventing memory deficits and neurochemical alterations observed in a model for Sporadic Dementia of Alzheimer's Type. Rats were treated with TA (30 mg/kg) daily for 21 days, and subsequently received intracerebroventricular injection of streptozotocin (STZ). We observed that STZ induced learning and memory impairments; however, treatment with TA was able to prevent these effects. In cerebral cortex and hippocampus, STZ induced an increase in acetylcholinesterase activity, reduced Na+, K+-ATPase activity and induced oxidative stress increasing thiobarbituric acid-reactive substances, nitrites and reactive oxygen species levels and reducing the activity of antioxidant enzymes. Treatment with TA was able in prevent the major of these neurochemical alterations. In conclusion, TA prevented memory deficits, alterations in brain enzyme activities, and oxidative damage induced by STZ. Thus, TA can be an interesting strategy in the prevention of Sporadic Alzheimer's Disease.
Assuntos
Doença de Alzheimer , Acetilcolinesterase/metabolismo , Adenosina Trifosfatases , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Animais , Modelos Animais de Doenças , Aprendizagem em Labirinto , Oxirredução , Estresse Oxidativo , Ratos , Ratos Wistar , Estreptozocina/toxicidade , TaninosRESUMO
Hypermethioninemia is a disorder characterized by high plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO). Studies have reported associated inflammatory complications, but the mechanisms involved in the pathophysiology of hypermethioninemia are still uncertain. The present study aims to evaluate the effect of chronic administration of Met and/or MetO on phenotypic characteristics of macrophages, in addition to oxidative stress, purinergic system, and inflammatory mediators in macrophages. In this study, Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2 g/kg body weight and 0.09-0.3 g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. The results revealed that Met and/or MetO induce an M1/classical activation phenotype associated with increased levels of tumor necrosis factor alpha and nitrite, and reduced arginase activity. It was also found that Met and/or MetO alter the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as the levels of thiol and reactive oxygen species in macrophages. The chronic administration of Met and/or MetO also promotes alteration in the hydrolysis of ATP and ADP, as indicated by the increased activity of ectonucleotidases. These results demonstrate that chronic administration of Met and/or MetO promotes activated pro-inflammatory profile by inducing M1/classical macrophage polarization. Thus, the changes in redox status and purinergic system upon chronic Met and/or MetO exposure may contribute towards better understanding of the alterations consistent with hypermethioninemic patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/imunologia , Glicina N-Metiltransferase/deficiência , Macrófagos/imunologia , Metionina/análogos & derivados , Animais , Catalase/metabolismo , Polaridade Celular , Glutationa Peroxidase/metabolismo , Glicina N-Metiltransferase/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Metionina/administração & dosagem , Metionina/metabolismo , Metionina/farmacologia , Camundongos , Oxirredução , Estresse Oxidativo , Fenótipo , Superóxido Dismutase/metabolismoRESUMO
Tannic acid (TA) is a hydrolysable glycosidic polyphenol polymer of gallic acid, which possesses neuroprotective properties. The aim of this study was to evaluate the effect of TA treatment on cognitive performance and neurochemical changes in an experimental model of sporadic dementia of Alzheimer's type (SDAT) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) and to explore the potential cellular and molecular mechanisms underlying these effects. Adult male rats were divided into four groups: control, TA, STZ, and TA + STZ. Animals from TA and TA + STZ groups were treated with TA (30 mg/kg) daily, by gavage, for 21 days; others groups received water (1 mL/kg). Subsequently, an ICV injection of STZ (3 mg/kg) was administered into the lateral ventricles of animals from STZ and TA + STZ groups, while other groups received citrate buffer. Cognitive deficits (short-term memory), neuronal survival, neuroinflammation as well as expression of SNAP-25, Akt, and pAkt were evaluated in the cerebral cortex. TA treatment protected against the impairment of memory in STZ-induced SDAT. STZ promoted an increase in neuronal death and the levels of proinflammatory cytokines (IL-6 and TNF-α) and a decrease in Akt and pAkt expression; TA was able to restore these changes. Neither STZ nor TA altered SNAP-25 expression or the levels of IL-12 and IL-4 in the cerebral cortex. Our study highlights that treatment with TA prevents memory deficits and reestablishes Akt and pAkt expression, protecting against neuronal death and neuroinflammation in STZ-induced SDAT in rats.
Assuntos
Doença de Alzheimer/metabolismo , Mediadores da Inflamação/metabolismo , Transtornos da Memória/metabolismo , Proteínas Proto-Oncogênicas c-akt/biossíntese , Estreptozocina/toxicidade , Taninos/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/prevenção & controle , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Ratos Wistar , Taninos/farmacologiaRESUMO
Bipolar disorder is a chronic mood disorder characterized by episodes of mania and depression. The aim of this study was to investigate the effects of blackberry extract on behavioral parameters, oxidative stress and inflammatory markers in a ketamine-induced model of mania. Animals were pretreated with extract (200â¯mg/kg, once a day for 14 days), lithium chloride (45â¯mg/kg, twice a day for 14 days), or vehicle. Between the 8th and 14th days, the animals received an injection of ketamine (25â¯mg/kg) or vehicle. On the 15th day, thirty minutes after ketamine administration, the animals' locomotion was assessed using open-field apparatus. After the experiments, the animals were euthanized and cerebral structures were removed for neurochemical analyses. The results showed that ketamine treatment induced hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus and striatum. In contrast, pretreatment with the extract or lithium was able to prevent hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus, and striatum. In addition, IL-6 and IL-10 levels were increased by ketamine, while the extract prevented these effects in the cerebral cortex. Pretreatment with the extract was also effective in decreasing IL-6 and increasing the level of IL-10 in the striatum. In summary, our findings suggest that blackberry consumption could help prevent or reduce manic episodes, since this extract have demonstrated neuroprotective properties as well as antioxidant and anti-inflammatory effects in the ketamine-induced mania model.
Assuntos
Antocianinas , Frutas , Mania/metabolismo , Extratos Vegetais/farmacologia , Rubus , Animais , Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Catalase/efeitos dos fármacos , Catalase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/toxicidade , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ketamina/toxicidade , Cloreto de Lítio/farmacologia , Mania/induzido quimicamente , Mania/fisiopatologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Teste de Campo Aberto , Extratos Vegetais/química , Ratos , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Abstract Intense physical activity can increase oxidative stress and muscle damage in, causing fatigue and injury. Graduated compression stockings (GCS) can decrease these deleterious effects. The aim was to determine the acute effects of GCS on muscle damage and oxidative stress (OS) in garbage collectors. Thirteen garbage collectors, 25.4±5.2 years, participated using GCS or placebo stockings. Blood samples were collected at pre and post a working day and after 16 hours of rest. Markers of OS and muscle damage were evaluated. Two-way ANOVA (two conditions and two moments) was used for the analysis of the outcomes No significant differences were found for creatine kinase, catalase and glutathione peroxidase between the time and groups. There was a significant difference for the total thiol content and superoxide dismutase only in the control group (pre and post, p = 0.004). The use of GCS exerted acute protection against the increase of markers of OS, but did not contribute to attenuate muscle damage.
Resumo Atividade física intensa pode aumentar o estresse oxidativo e danos musculares, causando fadiga e lesões. As meias de compressão graduada (MCG) podem diminuir esses efeitos deletérios. O objetivo foi determinar os efeitos agudos da MCG no dano muscular e estresse oxidativo (EO) em coletores de lixo. Treze coletores de lixo, 25,4 ± 5,2 anos, participaram usando MCG ou placebo. As amostras de sangue foram coletadas antes e após um dia útil e após 16 horas de descanso. Marcadores de EO e dano muscular foram avaliados. ANOVA de duas vias (duas condições e dois momentos) foi usada para á análise dos resultados. Não foram encontradas diferenças significativas para creatina quinase, catalase e glutationa peroxidase entre o tempo e os grupos. Houve uma diferença significativa para o conteúdo total tiólico e superóxido dismutase apenas no grupo controle (pré e pós, p = 0,004). O uso de MCG exerceu proteção aguda contra o aumento de marcadores de EO, mas não contribuiu para atenuar danos musculares
RESUMO
Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Nanocápsulas/química , Piperidinas/toxicidade , Piperidinas/uso terapêutico , Polímeros/química , Tiazolidinas/toxicidade , Tiazolidinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores Tumorais/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Glioma/sangue , Glioma/patologia , Humanos , Luz , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Polímeros/síntese química , Ratos Wistar , Tiazolidinas/síntese química , Tiazolidinas/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Testes de Toxicidade , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Glioblastomas are the most devastating brain tumor characterized by chemoresistance development and poor prognosis. Macrophages are a component of tumor microenvironment related to glioma malignancy. The relation among inflammation, innate immunity and cancer is accepted; however, molecular and cellular mechanisms mediating this relation and chemoresistance remain unresolved. OBJECTIVE: Here we evaluated whether glioma sensitive or resistant to temozolomide (TMZ) modulate macrophage polarization and inflammatory pathways associated. The impact of glioma-macrophage crosstalk on glioma proliferation was also investigated. METHODS: GL261 glioma chemoresistance was developed by exposing cells to increasing TMZ concentrations over a period of 6months. Mouse peritoneal macrophages were exposed to glioma-conditioned medium or co-cultured directly with glioma sensitive (GL) or chemoresistant (GLTMZ). Macrophage polarization, in vitro and in vivo glioma proliferation, redox parameters, ectonucleotidase activity and ATP cytotoxicity were performed. RESULTS: GLTMZ cells were more effective than GL in induce M2-like macrophage polarization and in promote a strong immunosuppressive environment characterized by high IL-10 release and increased antioxidant potential, which may contribute to glioma chemoresistance and proliferation. Interestingly, macrophage-GLTMZ crosstalk enhanced in vitro and in vivo proliferation of chemoresistant cells, decreased ectonucleotidase activities, which was followed by increased macrophage sensitivity to ATP induced death. CONCLUSIONS: Results suggest a differential macrophage modulation by GLTMZ cells, which may favor the maintenance of immunosuppressive tumor microenvironment and glioma proliferation. GENERAL SIGNIFICANCE: The induction of immunosuppressive environment and macrophage education by chemoresistant gliomas may be important for tumor recovery after chemotherapy and could be considered to overcome chemoresistance development.
Assuntos
Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Glioma/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Polaridade Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Modelos Animais de Doenças , Glioma/metabolismo , Glioma/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Receptores Purinérgicos/genética , Temozolomida , Microambiente Tumoral/efeitos dos fármacosRESUMO
Methionine is an essential amino acid involved in critical metabolic process, and regulation of methionine flux through metabolism is important to supply this amino acid for cell needs. Elevation in plasma methionine commonly occurs due to mutations in methionine-metabolizing enzymes, such as methionine adenosyltransferase. Hypermethioninemic patients exhibit clinical manifestations, including neuronal and liver disorders involving inflammation and tissue injury, which pathophysiology is not completely established. Here, we hypothesize that alterations in macrophage inflammatory response may contribute to deleterious effects of hypermethioninemia. To this end, macrophage primary cultures were exposed to methionine (1 mM) and/or its metabolite methionine sulfoxide (0.5 mM), and M1/proinflammatory or M2/anti-inflammatory macrophage polarization was evaluated. In addition, inflammation-related pathways including oxidative stress parameters, as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities; reactive oxygen species (ROS) production, and purinergic signaling, as ATP/ADP/AMPase activities, were investigated. Methionine and/or methionine sulfoxide induced M1/classical macrophage activation, which is related to proinflammatory responses characterized by increased iNOS activity and TNF-α release. Further experiments showed that treatments promoted alterations on redox state of macrophages by differentially modulated SOD and CAT activities and ROS levels. Finally, methionine and/or methionine sulfoxide treatment also altered the extracellular nucleotide metabolism, promoting an increase of ATPase/ADPase activities in macrophages. In conclusion, these findings contribute to better understand the participation of proinflammatory responses in cell injury observed in hypermethioninemic patients.
Assuntos
Macrófagos/metabolismo , Metionina/análogos & derivados , Metionina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Cecropia species are widely used in traditional medicine by its anti-diabetic, anti-hypertensive and anti-inflammatory properties. In the present study, we investigated the neuroprotective and antioxidant effects of the crude aqueous extract from Cecropia pachystachya leaves in a rat model of mania induced by ketamine. The results indicated that ketamine treatment (25 mg/kg i.p., for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex and hippocampus, evaluated by increased lipid peroxidation, carbonyl protein formation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in hippocampus. Pretreatment of rats with C. pachystachya aqueous extract (200 and 400 mg/kg p.o., for 14 days) or with lithium chloride (45 mg/kg p.o., for 14 days, used as a positive control) prevented both behavioral and pro-oxidant effects of ketamine. These findings suggest that C. pachystachya might be a useful tool for preventive intervention in bipolar disorder, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder .
Assuntos
Transtorno Bipolar/prevenção & controle , Ketamina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Urticaceae/química , Animais , Comportamento Animal , Cromatografia Líquida de Alta Pressão , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos WistarRESUMO
Chronic stressful stimuli influence disease susceptibility to depression, cardiovascular, metabolic and neurodegenerative disorders. The present work investigated antidepressant and antioxidant properties of the aqueous extract from Cecropia pachystachya in a mouse model of chronic unpredictable stress (CUS). Our results indicated that acute administration of the aqueous extract (AE) from C. pachystachya (200 and 400mg/kg, p.o.) produced an antidepressant-like effect in the forced swimming test (FST). The chronic treatment with C. pachystachya extract (200mg/kg, p.o., for 14 days) prevented the depressant-like effect but not the anxiogenic effect induced by CUS. In addition to the behavioral modifications, the 14 days of CUS increased lipid peroxidation in the hippocampus (HP) and prefrontal cortex (PFC), decreased total thiol content and glutathione peroxidase activity in the HP. C. pachystachya AE administration during CUS protocol was able to prevent the oxidative damage induced by stress. However, no changes were observed in the activity of the antioxidant enzymes superoxide dismutase and catalase in the above cited brain areas after the stress protocol and treatment. Our results suggest that C. pachystachya prevented both depressive behavior and oxidative damage induced by CUS, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by chronic stress.
Assuntos
Antidepressivos/farmacologia , Cecropia , Depressão/prevenção & controle , Extratos Vegetais/farmacologia , Estresse Psicológico/prevenção & controle , Animais , Antidepressivos/administração & dosagem , Ansiedade/prevenção & controle , Doença Crônica , Modelos Animais de Doenças , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/administração & dosagemRESUMO
The antioxidant properties of two series of thiazolidinones and thiazinanones were reported. The novel six-membered thiazinanones were synthesized from the efficient multicomponent reaction of 2-picolylamine (2-aminomethylpyridine), arenaldehydes, and the 3-mercaptopropionic acid in moderate to excellent yields. These novel compounds were fully identified and characterized by NMR and GC-MS techniques. In vitro antioxidant activities of all compounds were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) tests. The antioxidant assays of thiobarbituric acid reactive species and total thiol content levels in the cerebral cortex and liver of rats were also performed. Thiazinanone 5a showed the best radical scavenging activity in DPPH and ABTS tests, as well as reduced lipid peroxidation and increased total thiol group in biological systems. Altogether, the results may be considered a good starting point for the discovery of a new radical scavenger.
Assuntos
Sequestradores de Radicais Livres , Compostos Heterocíclicos com 3 Anéis , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Ratos , Ratos WistarRESUMO
Bipolar disorder (BD) is a chronic and debilitating illness characterized by recurrent manic and depressive episodes. Our research investigates the protective effects of curcumin, the main curcuminoid of the Indian spice turmeric, in a model of mania induced by ketamine administration in rats. Our results indicated that ketamine treatment (25 mg/kg, for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex (PFC) and hippocampus (HP), evaluated by increased lipid peroxidation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in the HP. Pretreatment of rats with curcumin (20 and 50 mg/kg, for 14 days) or with lithium chloride (45 mg/kg, positive control) prevented behavioral and pro-oxidant effects induced by ketamine. These findings suggest that curcumin might be a good compound for preventive intervention in BD, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder.
Assuntos
Antimaníacos/uso terapêutico , Antioxidantes/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Curcumina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Antimaníacos/farmacologia , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Catalase/metabolismo , Curcumina/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ketamina , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
In the present study, we reported the efficient synthesis of 11 3-(pyrimidin-2-yl)-thiazolidinones in good yields using molecular sieve as the desiccant agent. In addition, we have evaluated the antioxidant capacity of the synthesized compounds by the 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPHâ¢) and the 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS(+â¢) ) radicals scavenging assay. Six compounds showed antioxidant activity towards DPPH⢠(EC50 between 16.13 and 49.94 µg/mL) and also demonstrated excellent activity regarding ABTS(+â¢) (TEAC: 10.32-53.52). These results showed that compounds 3-(pyrimidin-2-yl)-thiazolidinones may be easily synthesized by a less expensive procedure and could be a good starting point to the development of new antioxidant compounds.
Assuntos
Antioxidantes/química , Antioxidantes/síntese química , Pirimidinas/química , Tiazolidinas/química , Tiazolidinas/síntese química , Benzotiazóis/química , Sequestradores de Radicais Livres/química , Oxirredução , Ácidos Sulfônicos/químicaRESUMO
The Biginelli reaction is a multicomponent reaction involving the condensation between an aldehyde, a ß-ketoester, and urea or thiourea, in the presence of an acid catalyst, producing dihydropyrimidinones (DHPMs). Owing to their important pharmacological properties, the DHPMs have been studied by many authors. However, most of the methodologies used for the synthesis of these compounds require drastic reaction conditions. In the current study, we report an efficient and clean procedure for preparing DHPMs by the use of citric acid or tartaric acid as a promoter of the Biginelli synthesis in ethanol as solvent. In addition, we have evaluated the antioxidant capacity of the compounds synthesized by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and the thiobarbituric acid-reactive species test. Two compounds presented antioxidant activity and also reduced lipid peroxidation at concentrations of 200 and 300 µM. In summary, we report an environmentally friendly procedure for the preparation of DHPMs and demonstrate the antioxidant capacity of some of the compounds.
Assuntos
Antioxidantes/síntese química , Ácido Cítrico/química , Pirimidinonas/síntese química , Tartaratos/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Etanol/química , Peroxidação de Lipídeos/efeitos dos fármacos , Pirimidinonas/química , Pirimidinonas/farmacologia , Ratos , Ratos Wistar , Solventes/químicaRESUMO
Considering that Na(+),K(+)-ATPase is an embedded-membrane enzyme and that experimental chronic hyperprolinemia decreases the activity of this enzyme in brain synaptic plasma membranes, the present study investigated the effect of chronic proline administration on thiobarbituric acid-reactive substances, as well as the influence of antioxidant vitamins E plus C on the effects mediated by proline on Na(+),K(+)-ATPase activity in cerebral cortex of rats. The expression of Na(+),K(+)-ATPase catalytic subunits was also evaluated. Results showed that proline increased thiobarbituric acid-reactive substances, suggesting an increase of lipid peroxidation. Furthermore, concomitant administration of vitamins E plus C significantly prevented the increase of lipid peroxidation, as well as the inhibition of Na(+),K(+)-ATPase activity caused by proline. We did not observe any change in levels of Na(+),K(+)-ATPase mRNA transcripts after chronic exposure to proline and vitamins E plus C. These findings provide insights into the mechanisms through which proline exerts its effects on brain function and suggest that treatment with antioxidants may be beneficial to treat neurological dysfunctions present in hyperprolinemic patients.
Assuntos
Antioxidantes , Ácido Ascórbico , Córtex Cerebral/enzimologia , Peroxidação de Lipídeos/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , Vitamina E , 1-Pirrolina-5-Carboxilato Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Análise de Variância , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacologia , Córtex Cerebral/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Prolina/administração & dosagem , Prolina/efeitos adversos , Prolina Oxidase/deficiência , Prolina Oxidase/metabolismo , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Membranas Sinápticas/efeitos dos fármacos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Vitamina E/metabolismo , Vitamina E/farmacologiaRESUMO
In the current study we initially investigated the influence of antioxidants (vitamins E plus C) on the effect mediated by acute and chronic administration of methionine (Met) on Na(+),K(+)-ATPase activity in rat hippocampus. We also verified whether the alterations on the enzyme after administration of Met and/or antioxidants were associated with changes in relative expression of Na(+),K(+)-ATPase catalytic subunits (isoforms α1, α2 and α3). For acute treatment, young rats received a single subcutaneous injection of Met or saline (control) and were sacrificed 12 h later. In another set of experiments, rats were pretreated for 1 week with daily intraperitoneal administration of vitamins E (40 mg/kg) and C (100 mg/kg) or saline. After that, rats received a single injection of Met or saline and were killed 12 h later. For chronic treatment, Met was administered to rats from the 6th to the 28th day of life; controls and treated rats were sacrificed 12 h after the last injection. In parallel to chronic treatment, rats received a daily intraperitoneal injection of vitamins E and C from the 6th to the 28th day of life and were killed 12 h after the last injection. Results showed that administration of antioxidants partially prevented the inhibition of enzyme activity caused by acute and chronic hypermethioninemia. Besides, we demonstrated that transcription of catalytic subunits of Na(+),K(+)-ATPase was not altered by chronic and acute exposure to Met and/or vitamins E plus C. These data strongly suggest the oxidative damage as one possible mechanism involved in the reduction of Na(+),K(+)-ATPase activity caused by hypermethioninemia and if confirmed in human beings, we might propose the use of antioxidants as an adjuvant therapy in hypermethioninemic patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/prevenção & controle , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Metionina/sangue , ATPase Trocadora de Sódio-Potássio/metabolismo , Vitamina E/farmacologia , Doença Aguda , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Animais , Doença Crônica , Humanos , Ratos , Ratos WistarRESUMO
We have previously demonstrated that early environment influences the metabolic response, affecting abdominal fat deposition in adult female rats exposed to a long-term highly caloric diet. In the present study, our goal was to verify the effects of the chronic exposure, in adulthood, to a highly palatable diet (chocolate) on cerebral Na+,K+-ATPase activity and S100B protein concentrations, and the response to its withdrawal in neonatally handled and non-handled rats. We measured the consumption of foods (standard lab chow and chocolate), body weight gain, S100B protein concentrations, as well as cerebral Na(+),K(+)-ATPase activity during chronic exposure and after chocolate withdrawal in adult female rats that had been exposed or not to neonatal handling (10 min/day, 10 first days of life). Non-handled rats chronically exposed to chocolate exhibited increased plasma S100B levels, but there was no difference in abdominal fat S100B concentration between groups. Chronic chocolate consumption decreased Na+,K+-ATPase activity in both amygdala and hippocampus in non-handled, but not in handled rats, and this effect disappeared after chocolate withdrawal. Non-handled animals also demonstrated increased frequency of head shaking in the open field after 24h of chocolate withdrawal in comparison to handled ones. These findings suggest that neonatal handling modifies the vulnerability to metabolic and brain alterations induced by chronic exposure to a highly palatable diet in adulthood.
Assuntos
Envelhecimento/metabolismo , Encéfalo/enzimologia , Carboidratos da Dieta/metabolismo , Privação de Alimentos/fisiologia , Fatores de Crescimento Neural/metabolismo , Proteínas S100/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100RESUMO
In the present study we evaluated the effect of chronic methionine administration on oxidative stress and biochemical parameters in liver and serum of rats, respectively. We also performed histological analysis in liver. Results showed that hypermethioninemia increased chemiluminescence, carbonyl content and glutathione peroxidase activity, decreased total antioxidant potential, as well as altered catalase activity. Hypermethioninemia increased synthesis and concentration of glycogen, besides histological studies showed morphological alterations and reduction in the glycogen/glycoprotein content in liver. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and glucose were increased in hypermethioninemic rats. These findings suggest that oxidative damage and histological changes caused by methionine may be related to the hepatic injury observed in hypermethioninemia.
Assuntos
Fígado/efeitos dos fármacos , Fígado/patologia , Metionina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Glutationa/metabolismo , Glicogênio/biossíntese , Humanos , Fígado/enzimologia , Fígado/metabolismo , Luminescência , Metionina/administração & dosagem , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Hyperhomocysteinemia has been related to various diseases, including homocystinuria, neurodegenerative and hepatic diseases. In the present study we initially investigated the effect of chronic homocysteine administration on some parameters of oxidative stress, named total radical-trapping antioxidant potential, total antioxidant reactivity, catalase activity, chemiluminescence, thiobarbituric acid-reactive substances, and total thiol content in liver of rats. We also performed histological analysis, evaluating steatosis, inflammatory infiltration, fibrosis, and glycogen/glycoprotein content in liver tissue sections from hyperhomocysteinemic rats. Finally, we evaluated the activities of aminotransferases in liver and plasma of hyperhomocysteinemic rats. Wistar rats received daily subcutaneous injection of Hcy from their 6th to their 28th day of life. Twelve hours after the last injection the rats were sacrificed, liver and plasma were collected. Hyperhomocysteinemia decreased antioxidant defenses and total thiol content, and increased lipid peroxidation in liver of rats, characterizing a reliable oxidative stress. Histological analysis indicated the presence of inflammatory infiltrate, fibrosis and reduced content of glycogen/glycoprotein in liver tissue sections from hyperhomocysteinemic rats. Aminotransferases activities were not altered by homocysteine. Our data showed a consistent profile of liver injury elicited by homocysteine, which could contribute to explain, at least in part, the mechanisms involved in human liver diseases associated to hyperhomocysteinemia.
Assuntos
Fibrose/patologia , Glicogênio/metabolismo , Glicoproteínas/metabolismo , Homocisteína/farmacologia , Inflamação/metabolismo , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/citologia , Fígado/patologia , Masculino , Ratos , Compostos de Sulfidrila/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
We have previously demonstrated that acute hyperhomocysteinemia induces oxidative stress in rat brain. In the present study, we initially investigated the effect of chronic hyperhomocysteinemia on some parameters of oxidative damage, namely total radical-trapping antioxidant potential and activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase), as well as on DNA damage in parietal cortex and blood of rats. We also evaluated the effect of folic acid on biochemical alterations elicited by hyperhomocysteinemia. Wistar rats received daily subcutaneous injection of Hcy (0.3-0.6 micromol/g body weight), and/or folic acid (0.011 micromol/g body weight) from their 6th to their 28th day of life. Twelve hours after the last injection the rats were sacrificed, parietal cortex and total blood was collected. Results showed that chronic homocysteine administration increased DNA damage, evaluated by comet assay, and disrupted antioxidant defenses (enzymatic and non-enzymatic) in parietal cortex and blood/plasma. Folic acid concurrent administration prevented homocysteine effects, possibly by its antioxidant and DNA stability maintenance properties. If confirmed in human beings, our results could propose that the supplementation of folic acid can be used as an adjuvant therapy in disorders that accumulate homocysteine.