RESUMEN

Elevated levels of methionine in blood characterize the hypermethioninemia, which may have genetic or non-genetic origin, as for example from high protein diet. Born rats from hypermethioninemic mothers presented cerebral oxidative stress, inhibition of Na+,K+-ATPase, memory deficit and ultrastructure cerebral changes. Melatonin is a hormone involved in circadian rhythm and has antioxidant effects. The aim of this study was to verify the possible neuroprotective effects of melatonin administration in hypermethioninemic pregnant rats on damage to biomolecules (Na+,K+-ATPase, sulfhydryl content and DNA damage index) and behavior (open field, novel object recognition and water maze tasks), as well as its effect on cells morphology by electron microscopy in offspring. Wistar female rats received methionine (2.68 µmol/g body weight) and/or melatonin (10 mg/kg body weight) by subcutaneous injections during entire pregnancy. Control rats received saline. Biochemical analyzes were performed at 21 and 30 days of life of offspring and behavioral analyzes were performed only at 30 days of age in male pups. Results showed that gestational hypermethioninemia diminished Na+,K+-ATPase activity and sulfhydryl content and increased DNA damage at 21 and 30 days of life. Melatonin was able to totally prevent Na+,K+-ATPase activity alteration at 21 days and partially prevent its alteration at 30 days of rats life. Melatonin was unable in to prevent sulfhydryl and DNA damage at two ages. It also improved DNA damage, but not at level of saline animals (controls). Regarding to behavioral tests, data showed that pups exposed to gestational hypermethioninemia decreased reference memory in water maze, spent more time to the center of the open field and did not differentiate the objects in the recognition test. Melatonin was able to prevent the deficit in novel object recognition task. Electron microscopy revealed ultrastructure alterations in neurons of hypermethioninemic at both ages of offspring, whose were prevented by melatonin. These findings suggest that melatonin may be a good neuroprotective to minimize the harmful effects of gestational hypermethioninemia on offspring.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Glicina N-Metiltransferasa/deficiencia , Melatonina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Complicaciones del Embarazo/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Melatonina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Embarazo , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos

RESUMEN

Although the use, and misuse, of methylphenidate is increasing in childhood and adolescence, there is little information about the consequences of this psychostimulant chronic use on brain and behavior during development. The aim of the present study was to investigate hippocampus biochemical, histochemical, and behavioral effects of chronic methylphenidate treatment to juvenile rats. Wistar rats received intraperitoneal injections of methylphenidate (2.0 mg/kg) or an equivalent volume of 0.9 % saline solution (controls), once a day, from the 15th to the 45th day of age. Results showed that chronic methylphenidate administration caused loss of astrocytes and neurons in the hippocampus of juvenile rats. BDNF and pTrkB immunocontents and NGF levels were decreased, while TNF-α and IL-6 levels, Iba-1 and caspase 3 cleaved immunocontents (microglia marker and active apoptosis marker, respectively) were increased. ERK and PKCaMII signaling pathways, but not Akt and GSK-3ß, were decreased. SNAP-25 was decreased after methylphenidate treatment, while GAP-43 and synaptophysin were not altered. Both exploratory activity and object recognition memory were impaired by methylphenidate. These findings provide additional evidence that early-life exposure to methylphenidate can have complex effects, as well as provide new basis for understanding of the biochemical and behavioral consequences associated with chronic use of methylphenidate during central nervous system development.

Asunto(s)

Astrocitos/patología , Conducta Animal/efectos de los fármacos , Hipocampo/patología , Metilfenidato/toxicidad , Neuronas/patología , Animales , Antígenos Nucleares/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Citocinas/metabolismo , Conducta Exploratoria/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Modelos Biológicos , Factores de Crecimiento Nervioso/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Reconocimiento en Psicología , Transducción de Señal , Proteína 25 Asociada a Sinaptosomas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

Mild hyperhomocysteinemia is considered to be a risk factor for cerebral and cardiovascular disorders and can be modeled in experimental rats. Inflammation has been implicated in the toxic effects of homocysteine. Cholinergic signaling controls cytokine production and inflammation through the "cholinergic anti-inflammatory pathway," and brain acetylcholinesterase activity plays a role in this regulation. The aim of this present study is to investigate the effect of mild chronic hyperhomocysteinemia on proinflammatory cytokine levels in the brain, heart, and serum of rats. Activity, immunocontent, and gene expression of acetylcholinesterase in the brain and butyrylcholinesterase activity in serum were also evaluated. Mild hyperhomocysteinemia was induced in Wistar rats by homocysteine administration (0.03 µmol/g of body weight) twice a day, from the 30th to the 60th days of life. Controls received saline in the same volumes. Results demonstrated an increase in tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and the chemokine monocyte chemotactic protein-1 (MCP-1) in the hippocampus, as well as an increase in IL-1ß and IL-6 levels in cerebral cortex. Acetylcholinesterase activity was increased in rats subjected to mild hyperhomocysteinemia in both cerebral structures tested; the immunocontent of this enzyme was also increased in the cerebral cortex and decreased in the hippocampus. Levels of acetylcholinesterase mRNA transcripts were not altered. Peripherally, homocysteine increased TNF-α, IL-6, and MCP-1 levels in the heart and IL-6 levels in serum. Taken altogether, these findings suggest that homocysteine promotes an inflammatory status that can contribute, at least in part, to neuronal and cardiovascular dysfunctions observed in mild hyperhomocysteinemia.

Asunto(s)

Acetilcolinesterasa/metabolismo , Corteza Cerebral/metabolismo , Citocinas/metabolismo , Hipocampo/metabolismo , Hiperhomocisteinemia/metabolismo , Animales , Corteza Cerebral/patología , Femenino , Hipocampo/patología , Inflamación/metabolismo , Inflamación/patología , ARN Mensajero/metabolismo , Ratas Wistar

RESUMEN

AIM: The effects of physical exercise on oxidative stress parameters and immunocontent of NF-кß/p65 in lung of rats submitted to lung injury, as well as its possible protective effect on the changes in the alveolar-capillary barrier (total cell count, lactate dehydrogenase and total protein) in the bronchoalveolar lavage fluid (BALF) and the inflammatory infiltration in the pulmonary parenchyma were evaluated. MAIN METHODS: Wistar rats were submitted to two months of physical exercise and after this period, lung injury was induced by intratracheal instillation of lipopolysaccharide (dose of 100 µg/100 g body weight). Twelve hours after injury, the animals were sacrificed and lung and BALF were collected. KEY FINDINGS: Results showed an increase in reactive species production, lipid peroxidation, oxidative damage to protein, as well as in nitrite levels and NF-кß/p65 immunocontent in lung of rats submitted to lung injury. Physical exercise was able to totally prevent the increase in reactive species, nitrite levels and NF-кß/p65 immunocontent, but partially prevented the damage to protein. Superoxide dismutase and catalase were not changed in lung injury group, but the activities of these enzymes were increased in lung injury plus exercise group. Non-enzymatic antioxidant capacity, glutathione content and glutathione peroxidase were decreased and exercise totally prevented such effects. Rats subjected to lung injury presented an increase in total cell, lactate dehydrogenase and total protein; exercise partially prevented the increase in lactate dehydrogenase. SIGNIFICANCE: These findings suggest that physical exercise may prevent, at least partially, the oxidative damage caused by experimental lung injury, suggesting that exercise may have an important role as protector in this condition.

Asunto(s)

Barrera Alveolocapilar/metabolismo , Lesión Pulmonar/metabolismo , Estrés Oxidativo , Condicionamiento Físico Animal , Animales , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/fisiopatología , Líquido del Lavado Bronquioalveolar , Catalasa/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Lipopolisacáridos/toxicidad , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/patología , Lesión Pulmonar/fisiopatología , Masculino , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Factor de Transcripción ReIA/metabolismo

RESUMEN

The use of psychostimulant methylphenidate has increased in recent years for the treatment of attention-deficit hyperactivity disorder in children and adolescents. However, the behavioral and neurochemical changes promoted by its use are not yet fully understood, particularly when used for a prolonged period during stages of brain development. Thus, the aim of this study was to determine some parameters of oxidative stress in encephalic structures of juvenile rats subjected to chronic methylphenidate treatment. Wistar rats received intraperitoneal injections of methylphenidate (2.0 mg/kg) once a day, from the 15th to the 45th day of age or an equivalent volume of 0.9% saline solution (controls). Two hours after the last injection, animals were euthanized and the encephalic structures obtained for determination of oxidative stress parameters. Results showed that methylphenidate administration increased the activities of superoxide dismutase and catalase, but did not alter the levels of reactive species, thiobarbituric acid reactive substances levels and sulfhydryl group in cerebellum of rats. In striatum and hippocampus, the methylphenidate-treated rats presented a decrease in the levels of reactive species and thiobarbituric acid reactive substances, but did not present changes in the sulfhydryl groups levels. In prefrontal cortex, methylphenidate promoted an increase in reactive species formation, SOD/CAT ratio, and increased the lipid peroxidation and protein damage. These findings suggest that the encephalic structures respond differently to methylphenidate treatment, at least, when administered chronically to young rats. Notably, the prefrontal cortex of juvenile rats showed greater sensitivity to oxidative effects promoted by methylphenidate in relation to other encephalic structures analyzed.

Asunto(s)

Estimulantes del Sistema Nervioso Central/toxicidad , Metilfenidato/toxicidad , Corteza Prefrontal/metabolismo , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Fluoresceínas , Glutatión Peroxidasa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inyecciones Intraperitoneales , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/fisiología , Corteza Prefrontal/patología , Ratas , Ratas Wistar , Especies de Nitrógeno Reactivo/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK-3ß) and cAMP response element-binding protein (CREB) through phosphatidylinositol 3-kinase (PI3-K)-dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four-vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK-3ß and CREB appear to play a critical role in resveratrol neuroprotection through the PI3-K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK-3ß and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3-K, compromised the neuroprotective effect of resveratrol and decreased the level of p-Akt, p-GSK-3ß and p-CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro-survival states of Akt, GSK-3ß and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3-K/Akt signaling pathway, subsequently downregulating expression of GSK-3ß and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats.

Asunto(s)

Isquemia Encefálica/metabolismo , Región CA1 Hipocampal/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Animales , Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/enzimología , Región CA1 Hipocampal/enzimología , Región CA1 Hipocampal/metabolismo , Cromonas/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Masculino , Morfolinas/farmacología , Neuronas/enzimología , Neuronas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Daño por Reperfusión/enzimología , Daño por Reperfusión/metabolismo , Resveratrol , Estilbenos/uso terapéutico

RESUMEN

The influence of physical exercise on the effects elicited by homocysteine on glutamate uptake and some parameters of oxidative stress, namely thiobarbituric acid-reactive substances, 2',7'-dichlorofluorescein (H(2)DCF) oxidation, as well as enzymatic antioxidant activities, superoxide dismutase, catalase and glutathione peroxidase in rat cerebral cortex were investigated. Wistar rats received subcutaneous administration of homocysteine or saline (control) from the 6th to 29th day of life. The physical exercise was performed from the 30th to 60th day of life; 12 h after the last exercise session animals were sacrificed and the cerebral cortex was dissected out. It is shown that homocysteine reduces glutamate uptake increases thiobarbituric acid-reactive substances and disrupts enzymatic antioxidant defenses in cerebral cortex. Physical activity reversed the homocysteine effects on glutamate uptake and on antioxidant enzymes activities; although the increase in thiobarbituric acid-reactive substances was only partially reversed by exercise. These findings allow us to suggest that physical exercise may have a protective role against homocysteine-induced oxidative imbalance and brain damage to the glutamatergic system.

Asunto(s)

Encefalopatías Metabólicas/terapia , Terapia por Ejercicio/métodos , Ácido Glutámico/metabolismo , Hiperhomocisteinemia/terapia , Estrés Oxidativo/fisiología , Condicionamiento Físico Animal/fisiología , Animales , Animales Recién Nacidos , Encefalopatías Metabólicas/fisiopatología , Modelos Animales de Enfermedad , Hiperhomocisteinemia/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar

RESUMEN

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.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Trastornos del Conocimiento/terapia , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Condicionamiento Físico Animal , 1-Pirrolina-5-Carboxilato Deshidrogenasa/deficiencia , Acetilcolinesterasa/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/psicología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Masculino , Prolina Oxidasa/deficiencia , Ratas , Ratas Wistar

RESUMEN

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.

Asunto(s)

Antioxidantes , Ácido Ascórbico , Corteza Cerebral/enzimología , Peroxidación de Lípido/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/efectos de los fármacos , Vitamina E , 1-Pirrolina-5-Carboxilato Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/inducido químicamente , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Análisis de Varianza , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacología , Corteza Cerebral/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Expresión Génica/efectos de los fármacos , Humanos , Estrés Oxidativo/efectos de los fármacos , Prolina/administración & dosificación , Prolina/efectos adversos , Prolina Oxidasa/deficiencia , Prolina Oxidasa/metabolismo , Ratas , Ratas Wistar , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Membranas Sinápticas/efectos de los fármacos , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Vitamina E/metabolismo , Vitamina E/farmacología

RESUMEN

Perinatal hypoxia-ischemia (HI) gives rise to inadequate substrate supply to the brain tissue, resulting in damage to neural cells. Previous studies at different time points of development, and with different animal species, suggest that the HI insult causes oxidative damage and changes Na+, K+-ATPase activity, which is known to be very susceptible to free radical-related lipid peroxidation. The aim of the present study was to establish the onset of the oxidative damage response in neonatal Wistar rats subjected to brain HI, evaluating parameters of oxidative stress, namely nitric oxide production, lipoperoxidation by thiobarbituric acid reactive substances (TBA-RS) production and malondialdehyde (MDA) levels, reactive species production by DCFH oxidation, antioxidant enzymatic activities of catalase, glutathione peroxidase, superoxide dismutase as well as Na+, K+-ATPase activity in hippocampus and cerebral cortex. Rat pups were subjected to right common carotid ligation followed by exposure to a hypoxic atmosphere (8% oxygen and 92% nitrogen) for 90 min. Animals were sacrificed by decapitation 0, 1 and 2 h after HI and both hippocampus and cerebral cortex from the right hemisphere (ipsilateral to the carotid occlusion) were dissected out for further experimentation. Results show an early decrease of Na+, K+-ATPase activity (at 0 and 1 h), as well as a late increase in MDA levels (2 h) and superoxide dismutase activity (1 and 2 h after HI) in the hippocampus. There was a late increase in both MDA levels and DCFH oxidation (1 and 2 h) and an increase in superoxide dismutase activity (2 h after HI) in cortex; however Na+, K+-ATPase activity remained unchanged. We suggest that neonatal HI induces oxidative damage to both hippocampus and cortex, in addition to a decrease in Na+, K+-ATPase activity in hippocampus early after the insult. These events might contribute to the later morphological damage in the brain and indicate that it would be essential to pursue neuroprotective strategies, aimed to counteract oxidative stress, as early as possible after the HI insult.

Asunto(s)

Encéfalo/fisiopatología , Hipoxia-Isquemia Encefálica/fisiopatología , Animales , Encéfalo/anatomía & histología , Encéfalo/patología , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Hipoxia-Isquemia Encefálica/patología , Malondialdehído/metabolismo , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Methylphenidate, a psychostimulant that affects both dopaminergic and noradrenergic systems, is one of the most frequently prescribed treatments for attention-deficit hyperactivity disorder. The present study investigated the effects of chronic administration of methylphenidate to juvenile rats on spatial memory, brain-derived neurotrophic factor immunocontent and acetylcholinesterase activity in hippocampus and prefrontal cortex. Rats received intraperitoneal injections of methylphenidate (2.0mg/kg) once a day, from the 15th to the 45th day of age or an equivalent volume of 0.9% saline solution (controls). Twenty-four hours after the last injection, animals were subjected to testing in the Morris water maze. After that, animals were sacrificed and hippocampus and prefrontal cortex were dissected out for determination of brain-derived neurotrophic factor immunocontent and acetylcholinesterase activity. Chronic administration of methylphenidate provoked cognitive impairments on spatial reference and working memory tasks. A reduction on brain-derived neurotrophic factor immunocontent and increased acetylcholinesterase activity in prefrontal cortex, but not in hippocampus, of rats treated with methylphenidate were also observed. These results suggest that the deficit in spatial memory may be associated to decreased brain-derived neurotrophic factor immunocontent and increased acetylcholinesterase in prefrontal cortex of juvenile rats subjected to methylphenidate administration.

Asunto(s)

Acetilcolinesterasa/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Metilfenidato/farmacología , Acetilcolinesterasa/metabolismo , Factores de Edad , Análisis de Varianza , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Inmunohistoquímica , Masculino , Aprendizaje por Laberinto/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiología , Estadísticas no Paramétricas

RESUMEN

The aim of this study was to investigate the effects of intrastriatal injection of hypoxanthine on ectonucleotidase (E-NTPDases and ecto-5'-nucleotidase) activities and expressions in the striatum of rats. The effect of pre-treatment with vitamins E and C on the effects elicited by this oxypurine on enzymatic activities and on thiobarbituric reactive substances (TBARS) was also investigated. The effect of pre-incubation with hypoxanthine on nucleotide hydrolysis in striatum homogenate was also determined. Adult Wistar rats were divided into (1) control and (2) hypoxanthine-injected groups. For ectonucleotidase activity determination, the animals were sacrificed at 30 min, 24 h and 7 days after drug infusion. For the evaluation of the expression of NTPDase 1-3 and also ecto-5'-nucleotidase, TBARS assay and the influence of the pre-treatment with vitamins on ectonucleotidase activities, the animals were sacrificed 24 h after hypoxanthine infusion. Results show that hypoxanthine infusion significantly inhibited ectonucleotidase activities and increased TBARS only 24 h after administration. Pre-treatment with vitamins was able to prevent these effects. Moreover, ecto-5'-nucleotidase expression was increased (80%) at 24 h after hypoxanthine infusion. We suggest that these hypoxanthine-induced biochemical modifications could, at least in part, participate in the pathophysiology of Lesch Nyhan disease.

Asunto(s)

Adenosina Trifosfatasas/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Hipoxantina/farmacología , 5'-Nucleotidasa/metabolismo , Animales , Antígenos CD/metabolismo , Apirasa/metabolismo , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/farmacología , Fármacos del Sistema Nervioso Central/administración & dosificación , Cuerpo Estriado/metabolismo , Hidrólisis/efectos de los fármacos , Hipoxantina/administración & dosificación , Masculino , Nucleótidos/metabolismo , Pirofosfatasas/metabolismo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de Tiempo , Vitamina E/administración & dosificación , Vitamina E/farmacología , Vitaminas/administración & dosificación , Vitaminas/farmacología

RESUMEN

Since a previous study has shown that ovariectomy impairs spatial memory, we, herein, investigate the influence of pre- and post-treatment with a soy diet on the effects elicited by ovariectomy on spatial memory. In the pre-treatment, 20-day-old female Wistar rats were first fed for 60 days on a standard diet with casein (control) or a soy diet. At 80 days of age, the animals were assigned to one of the following groups: sham (submitted to surgery without removal of ovaries) and ovariectomized. One week after surgery, the rats were submitted to behavioral testing. In the post-treatment, 80-day-old female rats were assigned to one of the following groups: sham and ovariectomized. One week after surgery, animals were fed for 30 days with the same diet described above. Then, rats were submitted to water maze testing. Pre-treatment for two months before ovariectomy with the soy diet effectively prevented the increase in latency in finding the platform on the fifth day of training in the ovariectomized group. Ovariectomized rats subjected to soy diet post-treatment reversed the increase in latency to find the platform in the ovariectomized group on the fifth day of training and, the decrease in the time spent in target quadrant, the increase in the time spent in opposite quadrant and the latency to cross the platform location. Results show that both pre- and post-treatment protected against the impairment of memory, caused by ovariectomy. Post-treatment reversed various parameters of memory reference, indicating that post-treatment was more efficient than pre-treatment. Based on these findings, we suggest that soy diet (rich in isoflavones) may represent a novel therapeutic strategy to prevent or to treat cognitive symptoms found in some menopausal women.

Asunto(s)

Glycine max/química , Isoflavonas/uso terapéutico , Memoria/efectos de los fármacos , Memoria/fisiología , Ovariectomía/psicología , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiología , Animales , Peso Corporal/efectos de los fármacos , Dieta , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Wistar

RESUMEN

Guanidinoacetate methyltransferase deficiency (GAMT-deficiency) is an inborn error of metabolism biochemically characterized by accumulation of guanidinoacetate (GAA) and depletion of creatine; the pathogenesis of brain dysfunction in this disorder is not yet established. In the present study we investigated the effect of intrastriatal administration of GAA on acetylcholinesterase (AChE) activity and on memory acquisition, consolidation and retrieval of step-down inhibitory avoidance task in rat. Results showed that GAA significantly increased AChE activity in rat striatum 30 min (50%) and 3 h (25%), but not 6 h after drug administration. GAA impaired test session performance when applied 30 min before training or after training, and before testing sessions, i.e., impaired memory acquisition, consolidation and retrieval. When injected with a 6 hour interval, GAA affected only memory retrieval. Although the mechanisms of action of GAA on AChE activity and on memory are unclear, these findings suggest that the accumulation of GAA found in patients with GAMT-deficiency may be one of the mechanisms involved in neural dysfunction. Further studies are necessary to evaluate these mechanisms.

Asunto(s)

Acetilcolinesterasa/metabolismo , Encefalopatías Metabólicas Innatas/enzimología , Cuerpo Estriado/enzimología , Discapacidades para el Aprendizaje/enzimología , Neuronas/enzimología , Acetilcolina/metabolismo , Acetilcolinesterasa/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Encefalopatías Metabólicas Innatas/inducido químicamente , Encefalopatías Metabólicas Innatas/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Glicina/análogos & derivados , Glicina/metabolismo , Glicina/toxicidad , Discapacidades para el Aprendizaje/inducido químicamente , Discapacidades para el Aprendizaje/fisiopatología , Neuronas/efectos de los fármacos , Ratas , Retención en Psicología/efectos de los fármacos , Retención en Psicología/fisiología , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología

RESUMEN

We investigated the hypothesis that folate administration would prevent hyperhomocysteinemia-induced memory deficits and Na(+),K(+)-ATPase activity inhibition. Chronic hyperhomocysteinemia was induced from the 6th to the 28th day of life by subcutaneous injection of homocysteine (0.3-0.6 micromol/g), twice a day; control Wistar rats received the same volume of saline solution (0.9% NaCl). Half of the homocysteine- and saline-treated groups also received intraperitoneal administration of folate (0.011 micromol/g) from the 6th to the 28th day of life. A group of animals was killed 12 h after the last injection, plasma and parietal cortex were collected for biochemical analysis. Another group stayed at Central Animal House until 60th day of life, when the rats were submitted to behavioral testing in water maze or were killed for evaluation of cortical Na(+),K(+)-ATPase activity. Results showed that hyperhomocysteinemia impaired reference memory for platform location, as assessed by fewer crossings to the platform place and increased latency for the first crossing, when compared to controls. In the working memory task homocysteine-treated animals also needed more time to find the platform. We also observed that Na(+),K(+)-ATPase activity was reduced in parietal cortex of hyperhomocysteinemic rats sacrificed 12h after the last injection of homocysteine (29-day-old rats). In contrast, this enzyme was not altered when the rats were sacrificed 31 days after the treatment (60-day-old rats). Hyperhomocysteinemic rats treated with folate had all those impairments prevented, an effect probably related to folate antioxidant properties.

Asunto(s)

Ácido Fólico/uso terapéutico , Hiperhomocisteinemia/etiología , Hiperhomocisteinemia/prevención & control , Trastornos de la Memoria/etiología , Trastornos de la Memoria/prevención & control , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Vitaminas/uso terapéutico , Envejecimiento/psicología , Animales , Enfermedad Crónica , Cognición/efectos de los fármacos , Homocisteína/sangre , Homocisteína/toxicidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Lóbulo Parietal/citología , Lóbulo Parietal/efectos de los fármacos , Ratas , Ratas Wistar , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Percepción Espacial/efectos de los fármacos , Membranas Sinápticas/efectos de los fármacos , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

1. S100B is a calcium-binding protein that acts as a neurotrophic cytokine and is expressed in the central nervous system, predominantly by astrocytes. At nanomolar concentrations, S100B stimulates neurite outgrowth and glial glutamate uptake, as well as protecting neurons against glutamate excitoxicity. 2. Peripheral S100B concentrations, particularly in the serum and cerebrospinal fluid (CSF), have been used as a parameter of glial activation or death in several physiological and pathological conditions. 3. In the present study, we investigated the effect of anaesthetics (thiopental, ketamine and halothane) on CSF concentrations of S100B, as well as a possible sex dependence, because several studies have suggested astrocytes as putative targets for oestrogen. 4. Higher levels of CSF S100B were found when rats were anaesthetized with thiopental; these levels, independently of anaesthetic, were sex dependent. Conversely, no effect of anaesthetic or sex was observed on serum concentrations of S100B. 5. The increase in CSF concentrations of S100B induced by thiopental was confirmed in non-anaesthetized neonatal rats and cortical astrocyte cultures. 6. Assuming CSF S100B as a marker of development, glial activation or even brain damage, investigations regarding the sex dependence of its concentration may be useful in gaining an understanding of sex variations in the behaviour and the pathological course of, as well as susceptibility to, many brain disorders. The findings of the present study reinforce the sex effect on synaptic plasticity and suggest a sex dependence of neural communication mediated by extracellular S100B without restricting the influence of astrocytes on the developmental phase.

Asunto(s)

Anestésicos/farmacología , Astrocitos/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Cisterna Magna/efectos de los fármacos , Halotano/farmacología , Ketamina/farmacología , Factores de Crecimiento Nervioso/líquido cefalorraquídeo , Proteínas S100/líquido cefalorraquídeo , Tiopental/farmacología , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Cisterna Magna/metabolismo , Femenino , Masculino , Ratas , Ratas Wistar , Subunidad beta de la Proteína de Unión al Calcio S100 , Factores Sexuales

RESUMEN

In the present study we investigated the effect of chronic hypermethioninemia on rat performance in the Morris water maze task, as well as on acetylcholinesterase (AChE) activity in rat cerebral cortex. For chronic treatment, rats received subcutaneous injections of methionine (1.34-2.68 micromol/g of body weight), twice a day, from the 6th to the 28th day of age; control rats received the same volume of saline solution. Groups of rats were killed 3 h, 12 h or 30 days after the last injection of methionine to AChE assay and another group was left to recover until the 60th day of life to assess the effect of early methionine administration on reference and working spatial memory of rats. AChE activity was also determined after behavioral task. Results showed that chronic treatment with methionine did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant days effect with significant differences between control and methionine-treated animals. Chronic hypermethioninemia significantly increased AChE activity at 3 h, 12 h or 30 days after the last injection of methionine, as well as before or after behavioral test. The effect of acute hypermethioninemia on AChE was also evaluated. For acute treatment, 29-day-old rats received one single injection of methionine (2.68 micromol/g of body weight) or saline and were killed 1, 3 or 12 h later. Results showed that acute administration of methionine did not alter cerebral cortex AChE activity. Our findings suggest that chronic experimental hypermethioninemia caused cognitive dysfunction and an increase of AChE activity that might be related, at least in part, to the neurological problems presented by hypermethioninemic patients.

Asunto(s)

Acetilcolinesterasa/metabolismo , Corteza Cerebral/enzimología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Metionina/sangre , Animales , Hipocampo/enzimología , Masculino , Ratas , Ratas Wistar

RESUMEN

OBJECTIVES: This study evaluated the effects of protein malnutrition on oxidative status in rat brain areas. METHODS: We investigated various parameters of oxidative status, free radical content (dichlorofluorescein formation), indexes of damage to lipid (thiobarbituric acid-reactive substances assay), and protein damage (tryptophan and tyrosine content) in addition to total antioxidant reactivity levels and antioxidant enzyme activities of superoxide dismutase, glutathione peroxidase, and catalase in different cerebral regions (cortex, hippocampus, and cerebellum) from rats subjected to prenatal and postnatal protein malnutrition (control 25% casein and protein malnutrition 7% casein). RESULTS: Protein malnutrition altered various parameters of oxidative stress, especially damage to macromolecules. Free radical content was unchanged by protein malnutrition. There was an increase in levels of thiobarbituric acid-reactive substances, the index of lipid peroxidation, in the cerebellum and cerebral cortex (P < 0.05) from protein-malnourished rats. Moreover, significant decreases in tryptophan and tyrosine in all tested brain structures (P < 0.05) were observed. Catalase activity was significantly decreased in the cerebellum (P < 0.05). In addition, a significant decrease in total antioxidant reactivity levels (P < 0.05) was observed in the cerebral cortex from protein-malnourished rats. CONCLUSIONS: The present data indicated that protein malnutrition increased oxidative damage to lipids and proteins from the studied brain areas. These results may be an indication of an important mechanism for changes in brain development that are caused by protein malnutrition.

Asunto(s)

Corteza Cerebelosa/efectos de los fármacos , Corteza Cerebelosa/metabolismo , Proteínas en la Dieta/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Deficiencia de Proteína/metabolismo , Animales , Catalasa/metabolismo , Corteza Cerebelosa/enzimología , Corteza Cerebelosa/crecimiento & desarrollo , Radicales Libres/análisis , Peroxidación de Lípido/efectos de los fármacos , Desnutrición , Estrés Oxidativo/fisiología , Fenómenos Fisiologicos de la Nutrición Prenatal , Distribución Aleatoria , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis

RESUMEN

It has been shown that emotional stress may induce oxidative damage, and considerably change the balance between pro-oxidant and antioxidant factors in the brain. The aim of this study was to verify the effect of repeated restraint stress (RRS; 1 h/day during 40 days) on several parameters of oxidative stress in the hippocampus of adult Wistar rats. We evaluated the lipid peroxide levels (assessed by TBARS levels), the production of free radicals (evaluated by the DCF test), the total radical-trapping potential (TRAP) and the total antioxidant reactivity (TAR) levels, and antioxidant enzyme activities (SOD, GPx and CAT) in hippocampus of rats. The results showed that RRS induced an increase in TBARS levels and in GPx activity, while TAR was reduced. We concluded that RRS induces oxidative stress in the rat hippocampus, and that these alterations may contribute to the deleterious effects observed after prolonged stress.

Asunto(s)

Hipocampo/metabolismo , Estrés Oxidativo/fisiología , Estrés Fisiológico/metabolismo , Animales , Hipocampo/fisiopatología , Masculino , Ratas , Ratas Wistar , Restricción Física , Estrés Fisiológico/fisiopatología

RESUMEN

Amazonian peoples use traditional remedies prepared with Ptychopetalum olacoides (PO) roots for treating various age-related conditions. This study shows that a single intraperitoneally (i.p.) administration of Ptychopetalum olacoides ethanol extract (POEE, 50 and 100mg/kg) improved memory retrieval in step-down inhibitory avoidance (P

Asunto(s)

Envejecimiento/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Memoria/efectos de los fármacos , Olacaceae , Envejecimiento/fisiología , Animales , Masculino , Memoria/fisiología , Ratones , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Raíces de Plantas , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología