RESUMO
The first 2 weeks of life are a critical period for neural development in rats. Repeated long-term separation from the dam is considered to be one of the most potent stressors to which rat pups can be exposed, and permanently modifies neurobiological and behavioral parameters. Prolonged periods of maternal separation (MS) usually increase stress reactivity during adulthood, and enhance anxiety-like behavior. The aim of this study was to verify the effects of maternal separation during the neonatal period on memory as well as on biochemical parameters (Na(+), K(+)-ATPase and antioxidant enzymes activities) in the amygdala of adult rats. Females and male Wistar rats were subjected to repeated maternal separation (incubator at 32 °C, 3 h/day) during postnatal days 1-10. At 60 days of age, the subjects were exposed to a Contextual fear conditioning task. One week after the behavioral task, animals were sacrificed and the amygdala was dissected for evaluation of Na(+), K(+)-ATPase and antioxidant enzymes activities. Student-t test showed significant MS effect, causing an increase of freezing time in the three exposures to the aversive context in both sexes. Considering biochemical parameters Student-t test showed significant MS effect causing an increase of Na(+), K(+)-ATPase activity in both sexes. On the other hand, no differences were found among the groups on the antioxidant enzymes activities [superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT)] in male rats, but in females, we found a significant MS effect, causing an increase of CAT activity and no differences were found among the groups on SOD and GPx activities. Our results suggest a role of early rearing environment in programming fear learning and memory in adulthood. An early stress experience such as maternal separation may increase activity in the amygdala (as pointed by the increased activity of Na(+), K(+)-ATPase), affecting behaviors related to fear in adulthood, and this effect could be task-specific.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico , Medo , Tonsila do Cerebelo/enzimologia , Animais , Catalase/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Masculino , Estresse Oxidativo , Gravidez , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Previous studies have demonstrated that early environmental interventions influence the consumption of palatable food and the abdominal fat deposition in female rats chronically exposed to a highly caloric diet in adulthood. In this study, we verified the metabolic effects of chronic exposure to a highly palatable diet, and determine the response to its withdrawal in adult neonatally handled and non-handled rats. Consumption of foods (standard lab chow and chocolate), body weight gain, abdominal fat deposition, plasma triglycerides, and leptin, as well as serum butyrylcholinesterase (BuChE), and cerebral acetylcholinesterase (AChE) activities were measured during chronic chocolate exposure and after deprivation of this palatable food in female rats exposed or not to neonatal handling (10 minutes/day, 10 first days of life). Handled rats increased rebound chocolate consumption in comparison to non-handled animals after 1 week of chocolate withdrawal; these animals also decreased body weight in the first 24 hours but this effect disappeared after 7 days of withdrawal. Chocolate increased abdominal fat in non-handled females, and this effect remained after 30 days of withdrawal; no differences in plasma leptin were seen after 7 days of withdrawal. Chocolate also increased serum BuChE activity in non-handled females, this effect was still evident after 7 days of withdrawal, but it disappeared after 30 days of withdrawal. Chocolate deprivation decreased cerebral AChE activity in both handled and non-handled animals. These findings suggest that neonatal handling modulates the preference for palatable food and induces a specific metabolic response that may be more adaptive in comparison to non-handled rats.
Assuntos
Animais Recém-Nascidos/fisiologia , Comportamento Animal , Dieta , Meio Ambiente , Manobra Psicológica , Gordura Abdominal , Acetilcolinesterase/metabolismo , Adaptação Psicológica , Animais , Encéfalo/enzimologia , Butirilcolinesterase/sangue , Cacau , Ingestão de Energia , Comportamento Alimentar/psicologia , Feminino , Preferências Alimentares/psicologia , Leptina/sangue , Obesidade Abdominal/etiologia , Obesidade Abdominal/psicologia , Gravidez , Ratos , Ratos Wistar , Estresse Psicológico , Síndrome de Abstinência a Substâncias , Triglicerídeos/sangue , Aumento de PesoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder whose pathogenesis involves production and aggregation of amyloid-ß peptide (Aß). Aß-induced toxicity is believed to involve alterations on as Na(+),K(+)-ATPase and acetylcholinesterase (AChE) activities, prior to neuronal death. Drugs able to prevent or to reverse these biochemical changes promote neuroprotection. GM1 is a ganglioside proposed to have neuroprotective roles in AD models, through mechanisms not yet fully understood. Therefore, this study aimed to investigate the effect of Aß1-42 infusion and GM1 treatment on recognition memory and on Na(+),K(+)-ATPase and AChE activities, as well as, on antioxidant defense in the brain cortex and the hippocampus. For these purposes, Wistar rats received i.c.v. infusion of fibrilar Aß1-42 (2 nmol) and/or GM1 (0.30 mg/kg). Behavioral and biochemical analyses were conducted 1 month after the infusion procedures. Our results showed that GM1 treatment prevented Aß-induced cognitive deficit, corroborating its neuroprotective function. Aß impaired Na(+),K(+)-ATPase and increase AChE activities in hippocampus and cortex, respectively. GM1, in turn, has partially prevented Aß-induced alteration on Na(+),K(+)-ATPase, though with no impact on AChE activity. Aß caused a decrease in antioxidant defense, specifically in hippocampus, an effect that was prevented by GM1 treatment. GM1, both in cortex and hippocampus, was able to increase antioxidant scavenge capacity. Our results suggest that Aß-triggered cognitive deficit involves region-specific alterations on Na(+),K(+)-ATPase and AChE activities, and that GM1 neuroprotection involves modulation of Na(+),K(+)-ATPase, maybe by its antioxidant properties. Although extrapolation from animal findings is difficult, it is conceivable that GM1 could play an important role in AD treatment.
Assuntos
Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/farmacologia , Gangliosídeo G(M1)/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Animais , Injeções Intraventriculares , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacosRESUMO
The present study investigated the effects of chronic hyperprolinemia on oxidative and metabolic status in liver and serum of rats. Wistar rats received daily subcutaneous injections of proline from their 6th to 28th day of life. Twelve hours after the last injection the rats were sacrificed and liver and serum were collected. Results showed that hyperprolinemia induced a significant reduction in total antioxidant potential and thiobarbituric acid-reactive substances. The activities of the antioxidant enzymes catalase and superoxide dismutase were significantly increased after chronic proline administration, while glutathione (GSH) peroxidase activity, dichlorofluorescin oxidation, GSH, sulfhydryl, and carbonyl content remained unaltered. Histological analyses of the liver revealed that proline treatment induced changes of the hepatic microarchitecture and increased the number of inflammatory cells and the glycogen content. Biochemical determination also demonstrated an increase in glycogen concentration, as well as a higher synthesis of glycogen in liver of hyperprolinemic rats. Regarding to hepatic metabolism, it was observed an increase on glucose oxidation and a decrease on lipid synthesis from glucose. However, hepatic lipid content and serum glucose levels were not changed. Proline administration did not alter the aminotransferases activities and serum markers of hepatic injury. Our findings suggest that hyperprolinemia alters the liver homeostasis possibly by induction of a mild degree of oxidative stress and metabolic changes. The hepatic alterations caused by proline probably do not implicate in substantial hepatic tissue damage, but rather demonstrate a process of adaptation of this tissue to oxidative stress. However, the biological significance of these findings requires additional investigation.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Prolina/administração & dosagem , 1-Pirrolina-5-Carboxilato Desidrogenase/deficiência , Animais , Antioxidantes/análise , Glicemia/análise , Catalase/metabolismo , Feminino , Fluoresceínas/metabolismo , Glutationa/análise , Glutationa Peroxidase/metabolismo , Glicogênio/biossíntese , Lipídeos/biossíntese , Masculino , Prolina Oxidase/deficiência , Prolina Oxidase/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
This study was carried out to ascertain the effects of maternal separation (3 h per day) of mothers from their pups in the neonatal period in rats, which has been suggested to induce a depressive-like state, would have long lasting effects on different parameters including hippocampal Na(+), K(+)-ATPase activity, NO production, free radical production and antioxidant enzymes activities in dams. Fourty-eight Wistar rats were divided into 3 groups: control, brief separation (10 min) and long separation (3 h). The neonatal interventions were done on postpartum days 1-10. At 35 days post-partum the dams were killed and the hippocampal Na(+), K(+)-ATPase activity were measured, as well as the activity of the antioxidant enzymes catalase, glutathione peroxidase, superoxide dismutase, free radicals production, and the production of nitric oxide. Hippocampal Na(+), K(+)-ATPase activity was decreased in the brief separated group and in dams subjected to 3 h separation from their pups. A reduction in nitric oxide levels in the hippocampus in dams of the long separated group was also observed. It is concluded that the withdrawal of pups from their mothers make the mothers more susceptible to the development of neurochemical alterations that could be related to depressive features.
Assuntos
Comportamento Animal , Depressão/patologia , Modelos Animais de Doenças , Animais , Depressão/psicologia , Feminino , Hipocampo/enzimologia , Hipocampo/metabolismo , Óxido Nítrico/biossíntese , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
This study investigated the effects of acute and chronic hyperprolinemia on glutamate uptake, as well as some mechanisms underlying the proline effects on glutamatergic system in rat cerebral cortex. The protective role of guanosine on effects mediated by proline was also evaluated. Results showed that acute and chronic hyperprolinemia reduced glutamate uptake, Na(+), K(+)-ATPase activity, ATP levels and increased lipoperoxidation. GLAST and GLT-1 immunocontent were increased in acute, but not in chronic hyperprolinemic rats. Our data suggest that the effects of proline on glutamate uptake may be mediated by lipid peroxidation and disruption of Na(+), K(+)-ATPase activity, but not by decreasing in glutamate transporters. This probably induces excitotoxicity and subsequent energy deficit. Guanosine was effective to prevent most of the effects promoted by proline, reinforcing its modulator role in counteracting the glutamate toxicity. However, further studies are needed to assess the modulatory effects of guanosine on experimental hyperprolinemia.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Encéfalo/fisiopatologia , Ácido Glutâmico/metabolismo , Guanosina/farmacologia , Homeostase , Fármacos Neuroprotetores/farmacologia , 1-Pirrolina-5-Carboxilato Desidrogenase/deficiência , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Prolina Oxidase/deficiência , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
This study investigated the effects of chronic homocysteine administration on some parameters of inflammation, such as cytokines (TNF-α, IL-1ß and IL-6), chemokine CCL(2) (MCP-1), nitrite and prostaglandin E(2) levels, as well as on immunocontent of NF-κB/p65 subunit in hippocampus and/or serum of rats. Since acetylcholinesterase has been associated with inflammation, we also evaluated the effect of homocysteine on this enzyme activity in hippocampus of rats. Wistar rats received daily subcutaneous injections of homocysteine (0.3-0.6 µmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12 h after the last injection, rats were euthanized and hippocampus and serum were used. Results showed that chronic hyperhomocysteinemia significantly increased pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), chemokine CCL(2) (MCP-1) and prostaglandin E(2) in hippocampus and serum of rats at 1 and 12 h after the last injection of homocysteine. Nitrite levels increased in hippocampus, but decreased in serum at 1 h after chronic hyperhomocysteinemia. Acetylcholinesterase activity and immunocontent of citoplasmic and nuclear NF-κB/p65 subunit were increased in hippocampus of rats subjected to hyperhomocysteinemia at 1 h, but did not alter at 12 h after the last injection of homocysteine. According to our results, chronic hyperhomocysteinemia increases inflammatory parameters, suggesting that this process might be associated, at least in part, with the cerebrovascular and vascular dysfunctions characteristic of some homocystinuric patients.
Assuntos
Biomarcadores/sangue , Hipocampo/metabolismo , Hiper-Homocisteinemia/sangue , Acetilcolinesterase/sangue , Animais , Quimiocina CCL2/sangue , Dinoprostona/sangue , Homocistinúria/complicações , Homocistinúria/fisiopatologia , Interleucina-1beta/sangue , Interleucina-6/sangue , Nitritos/sangue , Ratos , Ratos Wistar , Fator de Transcrição RelA/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
The effects of neonatal handling and the absence of ovarian hormones on the olfactory memory related to a palatable food in adulthood were investigated. Oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of adult pre-puberty ovariectomized female rats handled or not in the neonatal period were also evaluated. Litters were non-handled or handled (10 min/day, days 1-10 after birth). Females from each litter were divided into: OVX (subjected to ovariectomy), sham, and intact. When adults, olfactory memory related to a palatable food (chocolate) was evaluate using the hole-board olfactory task. Additionally, oxidative stress parameters and Na+/K+-ATPase activity were measured in the hippocampus and olfactory bulb. No difference between groups was observed considering olfactory memory evaluation. Neonatal handled rats presented an increase in Na+/K+-ATPase activity in the hippocampus and in the olfactory bulb, compared to non-handled ones. Considering the surgical procedure, there was a decrease in Na+/K+-ATPase and catalase activities in sham and OVX groups, compared to intact animals in the olfactory bulb. We concluded that olfactory memory related to a palatable food in adulthood was not affected by neonatal handling or by pre-puberty surgery, with or without removal of ovaries. The difference observed between groups in catalase and Na+/K+-ATPase activity does not seem to be related to the olfactory memory. Additionally, the increase in Na+/K+-ATPase activity (an enzyme that maintains the neurochemical gradient necessary for neuronal excitability) induced by neonatal handling may be related to neuroplastic changes in the hippocampus and olfactory bulb.
Assuntos
Manobra Psicológica , Hipocampo/metabolismo , Memória/fisiologia , Bulbo Olfatório/metabolismo , Percepção Olfatória/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Ração Animal , Animais , Catalase/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Ovariectomia , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , PaladarRESUMO
Since mild hyperhomocysteinemia is a risk factor for cardiovascular and cerebral diseases and extracellular nucleotides/nucleosides, which are controlled by the enzymatic action of ectonucleotidases, can induce an immune response, in the present study, we investigated the effect of chronic mild hyperhomocysteinemia on ectonucleotidase activities and expression in lymphocytes from mesenteric lymph nodes and serum of adult rats. For the chronic chemically induced mild hyperhomocysteinemia, Hcy (0.03 µmol/g of body weight) or saline (control) were administered subcutaneously from the 30th to the 60th day of life. Results showed that homocysteine significantly decreased ATP, ADP, and AMP hydrolysis in lymphocytes of adult rats. E-NTPDases transcriptions were not affected, while the ecto-5'-nucleotidase transcription was significantly decreased in mesenteric lymph nodes of hyperhomocysteinemic rats. ATP, ADP, and AMP hydrolysis were not affected by homocysteine in rat serum. Our findings suggest that Hcy in levels similar to considered risk factor to development of vascular diseases modulates the ectonucleotidases, which could lead to a pro-inflammatory status.
Assuntos
5'-Nucleotidase/biossíntese , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Hiper-Homocisteinemia/metabolismo , Linfócitos/metabolismo , 5'-Nucleotidase/genética , Animais , Homocisteína/sangue , Hiper-Homocisteinemia/genética , Hiper-Homocisteinemia/patologia , Linfócitos/imunologia , Linfócitos/patologia , Mesentério , Ratos , Ratos WistarRESUMO
Learning and memory deficits occur in depression and other stress related disorders. Although the pathogenesis of cognitive impairment after stress has not been fully elucidated, factors such as oxidative stress and neurotrophins are thought to play possible roles. Here we investigated the effect of treatment with vitamin E (40 mg/kg) and vitamin C (100 mg/kg) on the effects elicited by chronic variable stress on rat performance in Morris water maze. Brain-derived neurotrophic factor (BDNF) immunocontent was also evaluated in hippocampus of rats. Sixty-day old Wistar rats were submitted to different stressors for 40 days (stressed group). Half of stressed group received administration of vitamins once a day, during the period of stress. Chronically stressed rats presented a marked decrease in reference memory in the water maze task as well as a reduced efficiency to find the platform in the working memory task. Rats treated with vitamins E and C had part of the above effects prevented, suggesting the participation of oxidative stress in such effects. The BDNF levels were not altered in hippocampus of stressed group when compared to controls. Our findings lend support to a novel therapeutic strategy, associated with these vitamins, to the cognitive dysfunction observed in depression and other stress related diseases.
Assuntos
Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Estresse Psicológico/psicologia , Vitamina E/uso terapêutico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
This study investigated whether physical exercise would reverse proline-induced performance deficits in water maze tasks, as well as its effects on brain-derived neurotrophic factor (BDNF) immunocontent and brain acetylcholinesterase (AChE) activity in Wistar rats. Proline administration followed partial time (6th-29th day of life) or full time (6th-60th day of life) protocols. Treadmill exercise was performed from 30th to 60th day of life, when behavioral testing was started. After that, animals were sacrificed for BDNF and AChE determination. Results show that proline impairs cognitive performance, decreases BDNF in cerebral cortex and hippocampus and increases AChE activity in hippocampus. All reported effects were prevented by exercise. These results suggest that cognitive, spatial learning/memory, deficits caused by hyperprolinemia may be associated, at least in part, to the decrease in BDNF levels and to the increase in AChE activity, as well as support the role of physical exercise as a potential neuroprotective strategy.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Transtornos Cognitivos/terapia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Condicionamento Físico Animal , 1-Pirrolina-5-Carboxilato Desidrogenase/deficiência , Acetilcolinesterase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/psicologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Masculino , Prolina Oxidase/deficiência , Ratos , Ratos WistarRESUMO
Tissue accumulation of homocysteine occurs in classical homocystinuria, a metabolic disease characterized biochemically by cystathionine ß-synthase deficiency. Vascular manifestations such as myocardial infarction, cerebral thrombosis, hepatic steatosis, and pulmonary embolism are common in this disease and poorly understood. In this study, we investigated the effect of chronic hyperhomocysteinemia on some parameters of oxidative stress (thiobarbituric acid-reactive substances, protein carbonyl content, 2',7'-dichlorofluorescein fluorescence assay, and total radical-trapping antioxidant potent) and activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in the rat lung. Reduced glutathione content and glucose 6-phosphate dehydrogenase activity, as well as nitrite levels, were also evaluated. Wistar rats received daily subcutaneous injections of Hcy (0.3-0.6 µmol/g body weight) from the 6th to the 28th days-of-age and the control group received saline. One and 12 h after the last injection, rats were killed and the lungs collected. Hyperhomocysteinemia increased lipid peroxidation and oxidative damage to protein, and disrupted antioxidant defenses (enzymatic and non-enzymatic) in the lung of rats, characterizing a reliable oxidative stress. In contrast, this amino acid did not alter nitrite levels. Our findings showed a consistent profile of oxidative stress in the lung of rats, elicited by homocysteine, which could explain, at least in part, the mechanisms involved in the lung damage that is present in some homocystinuric patients.
Assuntos
Hiper-Homocisteinemia/patologia , Pulmão/patologia , Estresse Oxidativo , Animais , Catalase/metabolismo , Doença Crônica , Fluoresceínas/metabolismo , Fluorescência , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Homocisteína/administração & dosagem , Homocisteína/farmacologia , Hiper-Homocisteinemia/enzimologia , Pulmão/enzimologia , Modelos Biológicos , Nitritos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
In the present study we investigate the effect of homocysteine on glutamate uptake, Na+,K+-ATPase, enzymatic antioxidant defenses, as well as reactive species levels in hippocampus of rats. The influence of vitamin C, a classic antioxidant, on the effects elicited by homocysteine was also tested. Results showed that chronic hyperhomocysteinemia decreased glutamate uptake and the activities of Na+,K+-ATPase, catalase and superoxide dismutase in hippocampus of rats. Reactive species levels were increased by chronic homocysteine administration. Concomitant administration of vitamin C significantly prevented these alterations caused by homocysteine. According to our results, it seems possible to suggest that the reduction in glutamate uptake and Na+,K+-ATPase activity may be mediated by oxidative stress, since vitamin C prevented these effects. We suggest that the administration of antioxidants should be considered as an adjuvant therapy to specific diet in homocystinuria.
Assuntos
Ácido Ascórbico/farmacologia , Ácido Glutâmico/metabolismo , Homocisteína/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homocistinúria/terapia , Hiper-Homocisteinemia/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
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
Hyperhomocysteinemia plays an etiologic role in the pathogenesis of disorders, including homocystinuria and neurodegenerative and cardiovascular diseases. In the present study, we studied the effect of acute administration of homocysteine, similar to that found in homocystinuria, on parameters of inflammation such as cytokines (TNF-alpha, IL-1beta and IL-6), chemokine CCL2 (MCP-1), nitrite and acute phase-proteins (C-reactive protein and alpha(1)-Acid glycoprotein) levels in brain and blood of rats. In addition, a differential count of blood leukocytes was performed. Wistar rats, aged 29 days, received a single subcutaneous injection of saline (control) or homocysteine (0.6 micromol/g body weight). Fifteen minutes, 1 h, 6 h or 12 h after the injection, the rats were sacrificed and serum, hippocampus and cerebral cortex were used. Results showed that homocysteine significantly increased proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and chemokine CCL2 (MCP-1) in serum, hippocampus and cerebral cortex. Nitrite levels also increased in hippocampus and cerebral cortex at 15 min, 1 h and 6 h, but not 12 h after homocysteine administration. Acute phase-protein levels were not altered by homocysteine. The percentage of neutrophils and monocytes significantly increased in blood at 15 min and 1 h, but not at 6 h and 12 h after acute hyperhomocysteinemia, when compared to the control group. Our results showed that acute administration of homocysteine increased inflammatory parameters, suggesting that inflammation might be associated, at least in part, with the neuronal and cardiovascular dysfunctions observed in homocystinuric patients.
Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Homocisteína/administração & dosagem , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Mediadores da Inflamação/sangue , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Proteína C-Reativa/metabolismo , Córtex Cerebral/química , Córtex Cerebral/metabolismo , Quimiocinas/sangue , Citocinas/sangue , Modelos Animais de Doenças , Esquema de Medicação , Glicoproteínas/metabolismo , Hipocampo/química , Hipocampo/metabolismo , Homocisteína/sangue , Hiper-Homocisteinemia/induzido quimicamente , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Orosomucoide , Ratos , Ratos WistarRESUMO
In the present study we investigated the effect of acute hyperprolinemia on some parameters of energy metabolism, including the activities of succinate dehydrogenase and cytocrome c oxidase and (14)CO(2) production from glucose and acetate in cerebral cortex of young rats. Lipid peroxidation determined by the levels of thiobarbituric acid-reactive substances, as well as the influence of the antioxidants alpha-tocopherol plus ascorbic acid on the effects elicited by Pro on enzyme activities and on the lipid peroxidation were also evaluated. Wistar rats of 12 and 29 days of life received one subcutaneous injection of saline or proline (12.8 or 18.2 micromol/g body weight, respectively) and were sacrificed 1 h later. In another set of experiments, 5- and 22-day-old rats were pretreated for a week with daily intraperitoneal administration of alpha-tocopherol (40 mg/kg) plus ascorbic acid (100 mg/kg) or saline. Twelve hours after the last injection, rats received one injection of proline or saline and were sacrificed 1 h later. Results showed that acute administration of proline significantly reduced cytochrome c oxidase activity and increased succinate dehydrogenase activity and (14)CO(2) production in cerebral cortex, suggesting that Pro might disrupt energy metabolism in brain of young rats. In addition, proline administration increased the thiobarbituric acid-reactive substances levels, which were prevented by antioxidants. These findings suggest that mitochondrial dysfunction and oxidative stress may be important contributors to the neurological dysfunction observed in some hyperprolinemic patients and that treatment with antioxidants may be beneficial in this pathology.
Assuntos
Encefalopatias Metabólicas/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Metabolismo Energético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Prolina/efeitos adversos , Fatores Etários , Envelhecimento/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Encefalopatias Metabólicas/induzido quimicamente , Córtex Cerebral/crescimento & desenvolvimento , Modelos Animais de Doenças , Sinergismo Farmacológico , Metabolismo Energético/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Prolina/metabolismo , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , alfa-Tocoferol/farmacologia , alfa-Tocoferol/uso terapêuticoRESUMO
Methylphenidate is a central nervous system stimulant used for the treatment of attention-deficit hyperactivity disorder. Na(+), K(+)-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that methylphenidate effects on central nervous system metabolism are poorly known and that Na(+), K(+)-ATPase is essential to normal brain function, the purpose of this study was to evaluate the effect of this drug on Na(+), K(+)-ATPase activity in the cerebrum of young and adult rats. For acute administration, a single injection of methylphenidate (1.0, 2.0, or 10.0 mg/Kg) or saline was given to rats on postnatal day 25 or postnatal day 60, in the young and adult groups, respectively. For chronic administration, methylphenidate (1.0, 2.0, or 10.0 mg/Kg) or saline injections were given to young rats starting at postnatal day 25 once daily for 28 days. In adult rats, the same regimen was performed starting at postnatal day 60. Our results showed that acute methylphenidate administration increased Na(+), K(+)-ATPase activity in hippocampus, prefrontal cortex, and striatum of young and adult rats. In young rats, chronic administration of methylphenidate also enhanced Na(+), K(+)-ATPase activity in hippocampus and prefrontal cortex, but not in striatum. When tested in adult rats, Na(+), K(+)-ATPase activity was increased in all cerebral structures studied. The present findings suggest that increased Na(+), K(+)-ATPase activity may be associated with neuronal excitability caused by methylphenidate.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cérebro/efeitos dos fármacos , Cérebro/enzimologia , Metilfenidato/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Envelhecimento , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cérebro/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/metabolismo , Masculino , Metilfenidato/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/enzimologia , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Pre-puberty is a critical period for the final maturation of the neural circuits that control energy homeostasis, as external stimuli such as exposure to diets and stress may influence the adaptive responses with long-term repercussions. Our aim is to investigate the effects of isolation stress during early life and of chronic access to palatable diets, rich in sugar or fat, on the metabolic profile (glycemia, plasma lipids, leptin and cholinesterase activity) and oxidative stress parameters in the livers of adult male rats. We observed changes mainly in animals that received the high-fat diet (increased body weight and abdominal fat in adults, as well as increased plasma glucose, and cholinesterase activity), and most of these effects were further increased by exposure to stress. High-fat diet also affected the rats' lipid profile (increased cholesterol, LDL-cholesterol and triglycerides); these effects were more marked in stressed animals. Additionally, exposure to stress led to an oxidative imbalance in the liver, by increasing production of reactive species, as well as the activity of antioxidant enzymes (superoxide dismutase and catalase); these effects were accentuated with the high-fat diet (which also caused a severe reduction in glutathione peroxidase activity). Taken together, these results show that the pre-pubertal period constitutes a critical window for stressful interventions during development, leading to alterations in metabolic parameters and increased oxidative stress during adulthood that may be more pronounced in animals that receive a high-fat diet.
Assuntos
Gordura Abdominal/crescimento & desenvolvimento , Glândulas Suprarrenais/crescimento & desenvolvimento , Envelhecimento/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Isolamento Social , Gordura Abdominal/efeitos dos fármacos , Gordura Abdominal/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Colinesterases/sangue , Gorduras na Dieta/farmacologia , Sacarose Alimentar/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Radicais Livres/metabolismo , Glutationa Peroxidase/metabolismo , Leptina/sangue , Fígado/efeitos dos fármacos , Masculino , Tamanho do Órgão , Ratos , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismoRESUMO
The present study investigated the effects of hyperprolinemia on oxidative damage to biomolecules (protein, lipids and DNA) and the antioxidant status in blood of rats. The influence of the antioxidants on the effects elicited by proline was also examined. Wistar rats received two daily injections of proline and/or vitamin E plus C (6th-28th day of life) and were killed 12h after the last injection. Results showed that hyperprolinemia induced a significant oxidative damage to proteins, lipids and DNA demonstrated by increased carbonyl content, malondialdehyde levels and a greater damage index in comet assay, respectively. The concomitant antioxidants administration to proline treatment completely prevented oxidative damage to proteins, but partially prevented lipids and DNA damage. We also observed that the non-enzymatic antioxidant potential was decreased by proline treatment and partially prevented by antioxidant supplementation. The plasma levels of vitamins E and C significantly increased in rats treated exogenously with these vitamins but, interestingly, when proline was administered concomitantly with vitamin E plus C, the levels of these vitamins were similar to those found in plasma of control and proline rats. Our findings suggest that hyperprolinemia promotes oxidative damage to the three major classes of macromolecules in blood of rats. These effects were accomplished by decrease in non-enzymatic antioxidant potential and decrease in vitamins administered exogenously, which significantly decreased oxidative damage to biomolecules studied. These data suggest that antioxidants may be an effective adjuvant therapeutic to limit oxidative damage caused by proline.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Antioxidantes/farmacologia , Dano ao DNA/efeitos dos fármacos , DNA/química , Lipídeos/química , Estresse Oxidativo/efeitos dos fármacos , Prolina Oxidase/deficiência , Proteínas/química , 1-Pirrolina-5-Carboxilato Desidrogenase/deficiência , Animais , Ácido Ascórbico/farmacologia , Suplementos Nutricionais , Masculino , Malondialdeído/metabolismo , Oxirredução , Prolina/química , Ratos , Ratos Wistar , Vitamina E/farmacologia , Vitaminas/farmacologiaRESUMO
OBJECTIVES: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats. METHODS: Young male Wistar rats received a single injection of fenproporex (6.25, 12.5, or 25 mg/kg intraperitoneally) or polysorbate 80 (control group). Two hours after the last injection, the rats were killed by decapitation and the brain was removed for evaluation of Na+, K+-ATPase activity. RESULTS: Fenproporex decreased Na+, K+-ATPase activity in the striatum of young rats at doses of 6.25, 12.5, and 25 mg/kg and increased enzyme activity in the hypothalamus at the same doses. Na+, K+-ATPase activity was not affected in the hippocampus or prefrontal cortex. CONCLUSION: Fenproporex administration decreased Na+, K+-ATPase activity in the striatum even in low doses. However, in the hypothalamus, Na+, K+-ATPase activity was increased. Changes in this enzyme might be the result of the effects of fenproporex on neuronal excitability.