RESUMEN
Consumption of energy-dense/high-fat diets is strongly and positively associated with overweight and obesity, which are associated with increase in the prevalence of certain chronic diseases. We evaluated the effect of hypercaloric/fat or normocaloric diets on some biochemical parameters in rats. Seventy-two rats were divided into four groups that were fed for 16 weeks with diets: normocaloric [9.12% soy oil, normocaloric soy oil (NSO)], hypercaloric olive oil [43.8% olive oil, hypercaloric olive oil (HOO)], hypercaloric saturated fat [43.8% saturated fat, hypercaloric saturated fat (HSF)] and normocaloric saturated fat [43.8% saturated fat, normocaloric saturated fat (NSF)]. HSF rats consumed more calories daily than the others and gained more retroperitoneal fat, although HSF and HOO rats had higher body weight. In liver, glycogen synthesis and concentration were higher in rats HSF and NSF. In plasma, total cholesterol (TC) levels were higher in HSF rats than in the others, and triacylglycerol (TAG) levels were lower in HOO and higher in HSF rats in relation to the others. In liver, TC and TAG were elevated in HSF, NSF and HOO rats. Paraoxonase 1 activity, which is related to high-density lipoprotein cholesterol and has anti-atherogenic role was lower in rats HSF. In HOO rats, glucose tolerance test was altered, but insulin tolerance test was normal. These results suggest that consumption of energy-dense/high-fat diets, both saturated or monounsaturated, causes damaging effects. However, more studies are necessary to understand the mechanisms by which these diets cause the metabolic alterations observed.
Asunto(s)
Glucemia/metabolismo , Dieta Alta en Grasa , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/administración & dosificación , Tejido Adiposo/metabolismo , Animales , Arildialquilfosfatasa/sangre , Colesterol/sangre , Colesterol/metabolismo , Ingestión de Energía , Heces/química , Prueba de Tolerancia a la Glucosa , Glucógeno/metabolismo , Homeostasis , Hígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Aceite de Oliva , Aceites de Plantas/administración & dosificación , Ratas , Ratas Wistar , Aceite de Soja/administración & dosificación , Triglicéridos/sangre , Triglicéridos/metabolismo , Aumento de PesoRESUMEN
We studied the effects of L-phenylalanine and alpha-methylphenylalanine on 32P in vitro incorporation into cytoskeletal proteins from cerebral cortex of 17-day-old rats. Slices of cerebral cortex were incubated in the absence or presence of increasing concentrations of L-phenylalanine, alpha-methylphenylalanine or L-phenylalanine plus alpha-methylphenylalanine for 1 h. The cytoskeletal fraction obtained from slices was incubated in the presence of the same drugs and the 32P in vitro incorporation into cytoskeletal proteins was measured. Addition of alpha-methylphenylalanine did not change 32P in vitro incorporation into the cytoskeletal proteins, but phenylalanine decreased the in vitro phosphorylation of beta tubulin. Furthermore, addition of L-phenylalanine plus alpha-methylphenylalanine decreased the in vitro phosphorylation of both 160 kDa neurofilaments and alpha-tubulin.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Proteínas del Citoesqueleto/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Animales , Corteza Cerebral/metabolismo , Técnicas In Vitro , Radioisótopos de Fósforo , Ratas , Ratas WistarRESUMEN
Accumulation of methylmalonic acid (MMA) in tissues and biological fluids is the biochemical hallmark of patients affected by the neurometabolic disorder known as methylmalonic acidemia (MMAemia). Although this disease is predominantly characterized by severe neurological findings, the underlying mechanisms of brain injury are not totally established. In the present study, we investigated the effect of MMA, as well as propionic (PA) and tiglic (TA) acids, whose concentrations are also increased but to a lesser extend in MMAemia, on total (tCK), cytosolic (Cy-CK) and mitochondrial (Mi-CK) creatine kinase (CK) activities from cerebral cortex of 30-day-old Wistar rats. Total CK activity (tCK) was measured in whole cell homogenates, whereas Cy-CK and Mi-CK were determined, respectively, in cytosolic and mitochondrial preparations from rat cerebral cortex. We verified that tCK and Mi-CK activities were significantly inhibited by MMA at concentrations as low as 1 mM, in contrast to Cy-CK which was not affected by the presence of the acid in the incubation medium. Furthermore, PA and TA, at concentrations as high as 5 mM, did not alter CK activity. We also observed that the inhibitions provoked by MMA were fully prevented by pre-incubation of the homogenates with reduced glutathione, suggesting that the inhibitory effect of MMA was possibly mediated by oxidation of essential thiol groups of the enzyme. Considering the importance of CK for brain metabolism homeostasis, our results suggest that inhibition of this enzyme by increased levels of MMA may contribute to the neurodegeneration of patients affected by MMAemia and explain previous reports showing an impairment of brain energy metabolism and a reduction of brain phosphocreatine levels caused by MMA.
Asunto(s)
Corteza Cerebral/enzimología , Creatina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Ácido Metilmalónico/farmacología , Mitocondrias/enzimología , Animales , Antioxidantes/farmacología , Corteza Cerebral/efectos de los fármacos , Crotonatos/farmacología , Citosol/efectos de los fármacos , Citosol/metabolismo , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Hemiterpenos , Técnicas In Vitro , Indicadores y Reactivos , Masculino , Mitocondrias/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I , Propionatos/farmacología , RatasRESUMEN
Neurological dysfunction is common in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathology of this disorder are poorly known. In the present study we investigated the effect of acute hyperleucinemia on plasma and brain concentrations of amino acids. Fifteen-day-old rats were injected subcutaneously with 6 micromol L-leucine per gram body weight. Controls received saline in the same volumes. The animals were sacrificed 30--120 min after injection, blood was collected and their brain rapidly removed and homogenized. The amino acid concentrations were determined by HPLC using orthophtaldialdehyde for derivatization and fluorescence for detection. The results showed significant reductions of the large neutral amino acids (LNAA) L-phenylalanine, L-tyrosine, L-isoleucine, L-valine and L-methionine, as well as L-alanine, L-serine and L-histidine in plasma and of L-phenylalanine, L-isoleucine, L-valine and L-methionine in brain, as compared to controls. In vitro experiments using brain slices to study the influence of leucine on amino acid transport and protein synthesis were also carried out. L-Leucine strongly inhibited [14C]-L-phenylalanine transport into brain, as well as the incorporation of the [14C]-amino acid mixture, [14C]-L-phenylalanine and [14C]-L-lysine into the brain proteins. Although additional studies are necessary to evaluate the importance of these effects for MSUD, considering previous findings of reduced levels of LNAA in plasma and CSF of MSUD patients during crises, it may be speculated that a decrease of essential amino acids in brain may lead to reduction of protein and neurotransmiter synthesis in this disorder.
Asunto(s)
Aminoácidos/metabolismo , Leucina/sangre , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Aminoácidos/sangre , Animales , Glucemia/análisis , Cromatografía Líquida de Alta Presión , Femenino , Insulina/sangre , Masculino , Enfermedad de la Orina de Jarabe de Arce/sangre , Ratas , Ratas WistarRESUMEN
Propionic and methylmalonic acidemic patients have severe neurologic symptoms whose etiopathogeny is still obscure. Since increase of lactic acid is detected in the urine of these patients, especially during metabolic decompensation when high concentrations of methylmalonate (MMA) and propionate (PA) are produced, it is possible that cellular respiration may be impaired in these individuals. Therefore, we investigated the effects of MMA and PA (1, 2.5 and 5mM), the principal metabolites which accumulate in these conditions, on the mitochondrial respiratory chain complex activities succinate: 2,6-dichloroindophenol (DCIP) oxireductase (complex II); succinate: cytochrome c oxireductase (complexII+CoQ+III); NADH: cytochrome c oxireductase (complex I+CoQ+complex III); and cytochrome c oxidase (COX) (complex IV) from cerebral cortex homogenates of young rats. The effect of MMA on ubiquinol: cytochrome c oxireductase (complex III) and NADH: ubiquinone oxireductase (complex I) activities was also tested. Control groups did not contain MMA and PA in the incubation medium. MMA significantly inhibited complex I+III (32-46%), complex I (61-72%), and complex II+III (15-26%), without affecting significantly the activities of complexes II, III and IV. However, by using 1mM succinate in the assay instead of the usual 16mM concentration, MMA was able to significantly inhibit complex II activity in the brain homogenates. In contrast, PA did not affect any of these mitochondrial enzyme activities. The effect of MMA and PA on succinate: phenazine oxireductase (soluble succinate dehydrogenase (SDH)) was also measured in mitochondrial preparations. The results showed significant inhibition of the soluble SDH activity by MMA (11-27%) in purified mitochondrial fractions. Thus, if the in vitro inhibition of the oxidative phosphorylation system is also expressed under in vivo conditions, a deficit of brain energy production might explain some of the neurological abnormalities found in patients with methylmalonic acidemia (MMAemia) and be responsible for the lactic acidemia/aciduria identified in some of them.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Transporte de Electrón/efectos de los fármacos , Ácido Metilmalónico/farmacología , Mitocondrias/efectos de los fármacos , Animales , Corteza Cerebral/enzimología , Corteza Cerebral/metabolismo , Metabolismo Energético , Mitocondrias/enzimología , Ratas , Ratas WistarRESUMEN
The in vitro effects of propionic and L-methylmalonic acids on some parameters of oxidative stress were investigated in the cerebral cortex of 21-day-old rats. Chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS) and total radical-trapping antioxidant capacity (TRAP) were measured in brain tissue homogenates in the presence of propionic or L-methylmalonic acids at concentrations ranging from 1 to 10mM. Both acids significantly increased chemiluminescence and TBA-RS and decreased TRAP, indicating a simulation of lipid peroxidation and a reduction of tissue antioxidant potential. Other organic acids tested which accumulate in some organic acidemias (suberic, sebacic, adipic, 3-methylglutaric and 4-hydroxybutyric acids) did not affect these parameters. This study provides evidence that free radical generation may participate in the neurological dysfunction of propionic and methylmalonic acidemias.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Ácido Metilmalónico/farmacología , Estrés Oxidativo , Propionatos/farmacología , Animales , Antioxidantes/metabolismo , Mediciones Luminiscentes , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Buffered propionic acid was injected s.c. into rats twice a day at 8 h intervals from the 6 to 21 days of age. Control rats received saline in the same volumes. The animals were weighed and killed by decapitation at 23 days. Whole brain and cerebral cortex were weighed and synaptic plasma membranes were prepared from cortex for the determination of Na+,K+-ATPase and Mg2+-ATPase activities. Body, whole brain and cortical weights were similar in the two groups, suggesting that propionic acid does not cause malnutrition in rats. Na+,K+-ATPase activity was significantly reduced by 30% in membranes from the propionate-treated group, whereas Mg2+-ATPase activity was not. In another set of experiments, synaptic plasma membranes were prepared from cerebral cortex of 23-day-old rats and incubated with propionic acid at final concentrations ranging from 0.1 to 2.0 mM. Na+,K+-ATPase activity, but not Mg2+-ATPase activity, was inhibited by 22-32%. Since propionic acid concentrations in plasma of chronically treated rats and of propionic acidemic children are of the same order of magnitude as those tested in vitro, the results suggest that the inhibition of Na+,K+-ATPase activity may be related to the neurological dysfunction of patients affected by propionic acidaemia.
Asunto(s)
ATPasa de Ca(2+) y Mg(2+)/antagonistas & inhibidores , Corteza Cerebral/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Propionatos/farmacología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Membranas Sinápticas/efectos de los fármacos , Animales , Inyecciones Subcutáneas , Propionatos/sangre , Ratas , Ratas WistarRESUMEN
Hyperargininemia is a metabolic disorder biochemically characterized by tissue accumulation of arginine (Arg) and other guanidino compounds (GC). Convulsions, lethargy and psychomotor delay are predominant clinical features of this disease. Considering that some GC are epileptogenic and cause a decrease in membrane fluidity and that Na+,K(+)-ATPase, a membrane-bound enzyme, is essential for cellular excitability and is decreased in experimental and human epilepsy, in the present study we determined the in vitro effects of Arg, N-acetylarginine (NAA), argininic acid (AA) and homoarginine (HA) on the activity of Na+,K(+)-ATPase in the synaptic plasma membrane from cerebral cortex of young rats in the hope to identify a possible mechanism for the brain damage in hyperargininemia. The results showed that all GC tested, except Arg, significantly inhibited Na+,K(+)-ATPase activity at concentrations similar to those observed in plasma and CSF of patients with hyperargininemia. In addition, competition between NAA, AA and HA for the binding to the enzyme was observed, suggesting a common binding site for the GC. It is therefore possible that the inhibitory effect of GC on Na+,K(+)-ATPase may be related to the brain dysfunction observed in hyperargininemia.
Asunto(s)
Arginina/sangre , Corteza Cerebral/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Guanidinas/farmacología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Animales , Corteza Cerebral/enzimología , Ratas , Ratas WistarRESUMEN
Hyperargininemia is a metabolic disorder biochemically characterized by tissue accumulation of arginine and other guanidino compounds. Convulsions, lethargy and psychomotor delay or cognitive deterioration are predominant clinical features of this disease. Although neurologic symptoms predominate in this disorder, their pathophysiology is still unknown. In the present study we investigated the in vitro effects of arginine, N-acetylarginine, argininic acid and homoarginine on some oxidative stress parameters in rat brain in the hope to identify a possible mechanism for the brain damage in hyperargininemia. Chemiluminescence, total radical-trapping antioxidant potential (TRAP), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities were measured in the cerebral cortex of rats in the presence of various concentrations of these compounds. The results showed that all guanidino compounds tested significantly increased chemiluminescence and decreased TRAP at concentrations similar to those observed in the tissue of hyperargininemic patients. Furthermore, these compounds inhibited CAT and GSH-Px activities to varying extents, with GSH-Px activity being more susceptible to their action. In turn, argininic acid inhibited all enzyme activities, and its main action was also directed towards GSH-Px. The results suggest that oxidative stress caused by guanidino compounds may be involved in the brain dysfunction amongst other potential pathophysiological mechanisms observed in hyperargininemia.
Asunto(s)
Arginina/análogos & derivados , Arginina/farmacología , Corteza Cerebral/metabolismo , Hiperargininemia/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factores de Edad , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Femenino , Glutatión Peroxidasa/metabolismo , Homoarginina/farmacología , Hiperargininemia/inducido químicamente , Técnicas In Vitro , Mediciones Luminiscentes , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Neurological dysfunction is common in patients with methylmalonic and propionic acidemias. However, the mechanisms underlying the neuropathology of these disorders are far from understood. In the present study we investigated the in vitro effects of methylmalonic (MMA) and propionic (PA) acids at various concentrations (1 microM-5 mM) on three parameters of the glutamatergic system, namely the basal and potassium-induced release of L-[3H]glutamate by synaptosomes, Na+-dependent L-[3H]glutamate uptake by synaptosomes and Na+-independent L-[3H]glutamate uptake by synaptic vesicles from cerebral cortex of male adult Wistar rats. The results showed that MMA significantly increased potassium-induced but not basal L-[3H]glutamate release from synaptosomes with no alteration in synaptosomal L-[3H]glutamate uptake. A significant reduction of L-[3H]glutamate incorporation into vesicles caused by MMA was also detected. In contrast, PA had no effect on these parameters. These findings indicate that MMA alters the glutamatergic system. Although additional studies are necessary to evaluate the importance of these observations for the neuropathology of methylmalonic acidemia, it is possible that the effects elicited by MMA may lead to excessive glutamate concentrations at the synaptic cleft, a fact that may explain previous in vivo and in vitro findings associating MMA with excitotoxicity.
Asunto(s)
Corteza Cerebral/metabolismo , Ácido Glutámico/metabolismo , Ácido Metilmalónico/farmacología , Propionatos/farmacología , Vesículas Sinápticas/metabolismo , Sinaptosomas/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/enzimología , L-Lactato Deshidrogenasa/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Potasio/farmacología , Ratas , Ratas Wistar , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/enzimología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/enzimologíaRESUMEN
Histidinemia is an inherited metabolic disorder caused by deficiency of histidase activity, which leads to tissue accumulation of histidine and its derivatives. Affected patients usually present with speech delay and mental retardation, although asymptomatic patients have been reported. Considering that the pathophysiology of the neurological dysfunction of histidinemia is not yet understood and since histidine has been considered a pro-oxidant agent, in the present study we investigated the effect of histidine and one of its derivatives, l-beta-imidazolelactic acid, at concentrations ranging from 0.1 to 10 mM, on various parameters of oxidative stress in cerebral cortex of 30-day-old Wistar rats. Chemiluminescence, total radical-trapping antioxidant potential (TRAP), thiobarbituric acid reactive substances (TBA-RS), and the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were measured in tissue homogenates in the presence of l-histidine or l-beta-imidazolelactic acid. We observed that l-histidine provoked an increase of chemiluminescence and a reduction of TRAP at concentrations of 2.5 mM and higher, while TBA-RS measurement, GSH-Px, CAT and SOD activities were not affected. Furthermore, l-beta-imidazolelactic acid provoked antioxidant effects at high concentrations (5-10 mM) as observed by the reduction of chemiluminescence, although this compound enhanced chemiluminescence at low concentrations (0.5-1 mM). These results suggest that in vitro oxidative stress is elicited by histidine but only at supraphysiological concentrations.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas Innatas/metabolismo , Corteza Cerebral/metabolismo , Histidina/metabolismo , Estrés Oxidativo/fisiología , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Animales , Encefalopatías Metabólicas Innatas/fisiopatología , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Radicales Libres/metabolismo , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Histidina/farmacología , Imidazoles/farmacología , Lactatos/farmacología , Mediciones Luminiscentes , Oxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
The main objective of the present study was to characterize the inhibition by phenylalanine and phenylpyruvate of ATP diphosphohydrolase activity in synaptosomes from the brain cortex of rats. This enzyme participates together with a 5'-nucleotidase in adenosine formation from the neurotransmitter, ATP, in the synaptic cleft. The inhibition of ATP diphosphohydrolase was competitive for nucleotide hydrolysis but 5'-nucleotidase was not affected by these metabolites. Furthermore, the two substances inhibited enzyme activity by acting at the same binding site. If the enzyme inhibition observed in vitro also occurs in the brain of PKU patients, it may promote an increase in ATP levels in the synaptic cleft. In this case, the neurotoxicity of ATP could possibly be one of the mechanisms leading to the characteristic brain damage of phenylketonuria.
Asunto(s)
Adenosina Trifosfato/metabolismo , Apirasa/metabolismo , Corteza Cerebral/enzimología , Fenilalanina/metabolismo , Fenilcetonurias/enzimología , Ácidos Fenilpirúvicos/metabolismo , Terminales Presinápticos/enzimología , 5'-Nucleotidasa/antagonistas & inhibidores , 5'-Nucleotidasa/metabolismo , Adenosina/biosíntesis , Adenosina Difosfato/metabolismo , Animales , Apirasa/antagonistas & inhibidores , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Hidrólisis/efectos de los fármacos , Cinética , Fenilalanina/farmacología , Fenilcetonurias/fisiopatología , Ácidos Fenilpirúvicos/farmacología , Terminales Presinápticos/efectos de los fármacos , Ratas , Ratas Wistar , SinaptosomasRESUMEN
Sustained levels of methylmalonate comparable to those of human methylmalonic acidemia were achieved in the blood of young rats from the 5th till the 25th day of life by injecting them subcutaneously with buffered methylmalonic acid (MMA) twice a day at 8-h intervals. A matched group of rats (controls) was treated with saline. The animals were weighed and killed by decapitation at 25 days of age. Cerebellum and cerebrum were weighed and their contents of protein, DNA and ganglioside N-acetylneuraminic acid (G-NeuAc), as well as the protein/DNA ratio determined. Body weight, cerebral and cerebellar weight did not differ in both groups. The concentrations of protein, DNA and the protein/DNA ratio were also similar in the experimental and control groups. The results indicate that MMA per se does not interfere with the appetite of the animals and does not affect cellular proliferation and growth in cerebrum and cerebellum. We also found that G-NeuAc concentration is significantly reduced in the cerebellum. Therefore, since a deficit of an important component of brain closely related to the dendritic surface (synaptogenesis) occurs in MMA-treated rats, it is tempting to speculate whether this alteration may be associated or even partly responsible for the mental retardation in patients affected by methylmalonic acidemia.
Asunto(s)
Química Encefálica/efectos de los fármacos , Cerebelo/metabolismo , Malonatos/farmacología , Ácido Metilmalónico/farmacología , Ácidos Neuramínicos/metabolismo , Animales , Peso Corporal/efectos de los fármacos , ADN/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
Elevated levels of propionate comparable to those of human propionic acidaemia were achieved in the blood of young rats by injecting subcutaneously buffered propionic acid (PPA) twice a day at 8-h intervals from the 6th to the 28th day of life. A matched group of animals (controls) was treated with the same volumes of saline. The animals were weighed and sacrificed by decapitation at 28, 35 or 60 days of age. Cerebellum and cerebrum were weighed and their protein and ganglioside N-acetylneuraminic acid (G-NeuAc) contents determined. Body, cerebral and cerebellar weights were similar in both groups, suggesting that PPA per se neither alters the appetite of the rats nor causes malnutrition. Brain protein concentration was also not affected by chronic administration of PPA, in contrast to G-NeuAc concentration which was significantly reduced in the cerebellum. Since ganglioside concentration is closely related to the dendritic surface and indirectly reflects synaptogenesis, our results of an important ganglioside deficit in the brain of PPA-treated animals may be related to the neurologic dysfunction characteristic of propionic acidaemic patients.
Asunto(s)
Cerebelo/metabolismo , Gangliósidos/antagonistas & inhibidores , Ácidos Neuramínicos/antagonistas & inhibidores , Propionatos/farmacología , Animales , Cerebelo/efectos de los fármacos , Gangliósidos/metabolismo , Ácidos Neuramínicos/metabolismo , Concentración Osmolar , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Sustained levels of leucine comparable to those of human Maple Syrup Urine Disease (MSUD) were achieved in blood and brain of rats by subcutaneous leucine administration twice a day from the 6th to the 28th day of life. Control rats were treated with saline in the same volumes. Behavioral studies using aversive and nonaversive tasks were performed during adult age. Chronic early leucine treatment impaired acquisition of a two-way shuttle avoidance task and altered habituation to an open field. Our results suggest that early postnatal leucine administration induces long-lasting behavioral deficits.
Asunto(s)
Conducta Animal/efectos de los fármacos , Leucina/sangre , Animales , Reacción de Prevención/efectos de los fármacos , Peso Corporal , Enfermedad Crónica , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Femenino , Humanos , Leucina/administración & dosificación , Leucina/farmacocinética , Masculino , Enfermedad de la Orina de Jarabe de Arce/sangre , Embarazo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Sustained levels of proline comparable to those of human type II hyperprolinemia were achieved in blood and brain of rats subcutaneous proline administration twice a day from the 6th till the 28th day of life. Control rats were treated with saline in the same volumes. Behavioral studies using aversive and nonaversive tasks were performed one week or one month after treatment. Proline treatment did not affect rats' performance in the inhibitory avoidance task, but reduced significantly habituation in the open field. Our results seem to indicate that early postnatal administration of proline to rats affects habituation to a novel environment. If this happens to be so the present tendency to consider hyperprolinemia as a benign condition should be revised.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Habituación Psicofisiológica/efectos de los fármacos , Prolina/farmacología , Factores de Edad , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/anatomía & histología , Química Encefálica , Femenino , Masculino , Tamaño de los Órganos/efectos de los fármacos , Prolina/sangre , Prolina/farmacocinética , Ratas , Ratas Endogámicas , Distribución TisularRESUMEN
High levels of propionic acid (PPA) comparable to those of human propionic acidemia were achieved in blood (1-5 mmol/l) and brain (1 micromol/g) of rats by administering saline-buffered propionate (pH 7.4) subcutaneously twice a day from the 6th to the 28th day of life. PPA doses ranged from 1.44 to 1.92 micromol/g body weight as a function of animal age. Control rats were treated with saline in the same volumes. Growth and development of physical landmarks were assessed by monitoring the following parameters daily: body weight, upper incisor eruption, eye opening, and hair coat. Development of some reflexes was also monitored, and a specific subset of motor skills was evaluated at days 14 and 21 of life by the free-fall righting test and the spontaneous alternation test. Chronic PPA administration had no effect on body weight, cerebral cortex weight, or cerebellum weight, but caused slight but significant delays in the day of appearance of hair coat and eye opening, indicating an effect of PPA on the development of physical parameters. Free-fall righting was impaired in PPA-treated animals. On the other hand, PPA administration had no effect on the performance of the animals in the spontaneous alternation tests. Long-term effects of early PPA administration were investigated by assessing animal performance in an aversive task (two-way shuttle avoidance task) and in a nonaversive (open-field task) behavioral task at 60 days of age. PPA-treated rats did not habituate to the open field, and presented a lack of retention of the shuttle-avoidance task. Our results suggest that early postnatal PPA administration to rats alters normal development and induces long-term behavioral deficits in aversive and nonaversive tasks.
Asunto(s)
Acidosis/psicología , Conducta Animal/efectos de los fármacos , Sistema Nervioso/crecimiento & desarrollo , Propionatos/sangre , Envejecimiento/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Cerebelo/crecimiento & desarrollo , Cerebelo/metabolismo , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Femenino , Crecimiento/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Embarazo , Propionatos/farmacocinética , Ratas , Ratas Wistar , Reflejo/efectos de los fármacosRESUMEN
Vitamin A decreased the urinary excretion of total mucopolysaccharides in a patient with Hurler-Scheie compound (type IH-S mucopolysaccharidosis). Vitamin A was administered orally in daily doses of 1,000 to 2,000 IU/kg body weight for 10 years. Adverse clinical responses such as irritability, bone pain, dizziness, vomiting and diarrhea appeared in the patient and were controlled by reduction of the dose administered. No clinical improvement was observed, although it is possible that the clinical course of the disease may have been retarded.
Asunto(s)
Glicosaminoglicanos/orina , Mucopolisacaridosis I/tratamiento farmacológico , Vitamina A/uso terapéutico , Adolescente , Sulfatos de Condroitina/orina , Dermatán Sulfato/orina , Relación Dosis-Respuesta a Droga , Femenino , Heparitina Sulfato/orina , Humanos , Síndrome , Vitamina A/administración & dosificaciónRESUMEN
Levels of methylmalonic acid (MMA) comparable to those of human methylmalonic acidemia were achieved in blood (2-2.5 mmol/l) and brain (1.35 umol/g) of rats by administering buffered MMA, pH 7.4, subcutaneously twice a day from the 5th to the 28th day of life. MMA doses ranged from 0.76 to 1.67 umol/g as a function of animal age. Control rats were treated with saline in the same volumes. The animals were sacrificed by decapitation on the 28th day of age. Blood was taken and the brain was rapidly removed. Medulla, pons, the olfactory lobes and cerebellum were discarded and the rest of the brain ("cerebrum") was isolated. Body and "cerebrum" weight were measured, as well as the cholesterol and triglyceride concentrations in blood and the content of myelin, total lipids, and the concentrations of the lipid fractions (cholesterol, glycerolipids, phospholipids and ganglioside N-acetylneuraminic acid (ganglioside-NANA)) in the "cerebrum". Chronic MMA administration had no effect on body or "cerebrum" weight, suggesting that the metabolites per se neither affect the appetite of the rats nor cause malnutrition. In contrast, MMA caused a significant reduction of plasma triglycerides, but not of plasma cholesterol levels. A significant diminution of myelin content and of ganglioside-NANA concentration was also observed in the "cerebrum". We propose that the reduction of myelin content and ganglioside-NANA caused by MMA may be related to the delayed myelination/cerebral atrophy and neurological dysfunction found in methylmalonic acidemic children.
Asunto(s)
Química Encefálica , Gangliósidos/metabolismo , Metabolismo de los Lípidos , Ácido Metilmalónico/administración & dosificación , Vaina de Mielina/efectos de los fármacos , Ácidos Siálicos/metabolismo , Animales , Animales Recién Nacidos , Colesterol/metabolismo , Femenino , Ácido Metilmalónico/farmacología , Fosfolípidos/metabolismo , Ratas , Ratas Wistar , Triglicéridos/metabolismoRESUMEN
Administration of methylmalonic acid in rats has been used as a model for methylmalonicacidemia in humans. Nestling Wistar rats of both sexes received 5 injections daily at 3-h intervals (starting at 7:30 a.m.) of saline or methylmalonic acid (MMA, 10 mg/ml) in a volume of 9 microliters/g body weight per injection subcutaneously in the lumbar region from the 5th to the 9th day of life and 11 microliters/g from day 10 to 14. Growth and neuromotor development were assessed by monitoring the following parameters daily in 54 rats: body weight, ear unfolding, incisor eruption, eye opening, righting, palmar grasp, negative geotaxis, cliff avoidance, free-fall righting and startle reflex. The only statistically significant effects of MMA administration were on the day of appearance of the free-fall righting reflex: MMA, 12.44 +/- 1.55 vs 11.0 +/- 0.39 days for saline control (P < 0.05, by two-way ANOVA) and a significant decrease in weight (P < 0.05, by ANOVA with repeated measures). The results suggest that chronic MMA administration to rats has a selective effect on neuromotor development.