RESUMEN
Ammonia is involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy. Few is known about the effects of gestational exposition to ammonia in the developing brain, and the possible long-term consequences of such exposure. We aimed to evaluate the effects of ammonia exposure during the gestation and the possible long-term cognitive alterations on pups. Eight female rats were divided into two groups: (1) control (saline solution); (2) ammonia (ammonium acetate, 2,5mmol/Kg). Each rat received a single subcutaneous injection during all gestational period. The brains from 1-day-old rats were obtained to the determination of thiobarbituric acid reactive species (TBARS), protein carbonyl and nitrite/nitrate levels. Some animals were followed 30 days after delivery and were subjected to the step-down inhibitory avoidance task. It was observed a significant increase in protein carbonyl, but not TBARS or nitrite/nitrate levels, in pups exposed to ammonia. Rats exposed to ammonia presented long-term cognitive impairment. Gestational exposition to ammonia induces protein oxidative damage in the neonatal rat brain, and long-term cognitive impairment.
Asunto(s)
Amoníaco , Encéfalo , Amoníaco/toxicidad , Animales , Cognición , Estrés Oxidativo , Embarazo , Ratas , Ratas WistarRESUMEN
Taurine (Tau) is an abundant amino acid in polymorphonuclear leukocytes that react with hypochlorous acid to form taurine chloramine (TauCl) under inflammatory conditions. We investigated potential interactions between lymphocytes and TauCl in rats submitted to cecal ligation. Animals were divided into sham or CLP groups (24 or 120 h) to isolate lymphocytes from blood and spleen. Lymphocytes were cultured at a concentration of 1×106 cells/mL and activated by concanavalin A. Tau and TauCl were added at 1, 10, and 100 µM. Cells were incubated with MTT to evaluate cell viability and cytokine concentration in the supernatant was determined. TauCl decreased lymphocyte viability and altered the secretion pattern of important inflammatory mediators in non-specific-phenotype manner. The effort to a is elucidate mechanisms of immune cell (dys)function in sepsis is important to better understand the complex regulation of immune system during sepsis development, and further studies are necessary to confirm TauCl as potential target in this context.
Asunto(s)
Sepsis , Bazo , Animales , Supervivencia Celular , Células Cultivadas , Citocinas , Linfocitos , Ratas , Taurina/análogos & derivados , Taurina/farmacologíaRESUMEN
Maple syrup urine disease (MSUD) is a rare metabolic disorder associated with acute and chronic brain dysfunction. This condition has been shown to lead to macroscopic cerebral alterations that are visible on imaging studies. Cerebral oedema is widely considered to be detrimental for MSUD patients; however, the mechanisms involved are still poorly understood. Therefore, we investigated whether acute administration of branched-chain amino acids (BCAA) causes cerebral oedema, modifies the Na(+),K(+)-ATPase activity, affects the permeability of the blood-brain barrier (BBB) and alters the levels of cytokines in the hippocampus and cerebral cortex of 10-day-old rats. Additionally, we investigated the influence of concomitant administration of dexamethasone on the alterations caused by BCAA. Our results showed that the animals submitted to the model of MSUD exhibited an increase in the brain water content, both in the cerebral cortex and in the hippocampus. By investigating the mechanism of cerebral oedema, we discovered an association between H-BCAA and the Na(+),K(+)-ATPase activity and the permeability of the BBB to small molecules. Moreover, the H-BCAA administration increases Il-1ß, IL-6 and TNF-α levels in the hippocampus and cerebral cortex, whereas IL-10 levels were decreased in the hippocampus. Interestingly, we showed that the administration of dexamethasone successfully reduced cerebral oedema, preventing the inhibition of Na(+),K(+)-ATPase activity, BBB breakdown and the increase in the cytokines levels. In conclusion, these findings suggest that dexamethasone can improve the acute cerebral oedema and brain injury associated with high levels of BCAA, either through a direct effect on brain capillary Na(+),K(+)-ATPase or through a generalized effect on the permeability of the BBB to all compounds.
Asunto(s)
Barrera Hematoencefálica/patología , Edema Encefálico/prevención & control , Dexametasona/uso terapéutico , Hipocampo/enzimología , Enfermedad de la Orina de Jarabe de Arce/complicaciones , Enfermedad de la Orina de Jarabe de Arce/tratamiento farmacológico , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Aminoácidos de Cadena Ramificada/administración & dosificación , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Edema Encefálico/complicaciones , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/patología , Dexametasona/administración & dosificación , Dexametasona/farmacología , Modelos Animales de Enfermedad , Hipocampo/patología , Masculino , Enfermedad de la Orina de Jarabe de Arce/enzimología , Enfermedad de la Orina de Jarabe de Arce/patología , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Acute leucine intoxication and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection or psychological stress in patients with maple syrup urine disease (MSUD). Here, we investigated the effects of acute and chronic Hyper-BCAA (H-BCAA) administration on pro- and anti-inflammatory cytokines in the brains of rats. For acute administration, Wistar rats (10 and 30 days) received three injections of BCAA pool (15.8 µL/g at 1-h intervals) or saline, subcutaneously. For chronic administration, Wistar rats (7 days) received of BCAA pool or saline twice a day for 21 days, subcutaneously. Our results showed that acute administration of H-BCAA increased IL-1ß (â¼ 78%; p ≤ 0.009) and TNF-α (â¼ 155%; p ≤ 0.026) levels in the cerebral cortex but not in the hippocampus of infant rats. Moreover, IL-6 levels were increased in the hippocampus (â¼ 135%; p ≤ 0.009) and cerebral cortex (â¼ 417%; p ≤ 0.008), whereas IL-10 levels were decreased only in the hippocampus (â¼ 42%; p ≤ 0.009). However, repeated administration of H-BCAA decreased IL-1ß (â¼ 59%; p ≤ 0.047), IL-6 (â¼ 70%; p ≤ 0.009) and IFN-γ (â¼ 70%; p ≤ 0.008) levels in the cerebral cortex, whereas the IL-6 (â¼ 67%; p ≤ 0.009), IL-10 (â¼ 58%; p ≤ 0.01) and IFN-γ (â¼ 67%; p ≤ 0.009) levels were decreased in the hippocampus. These findings suggest that a better understanding of the inflammatory response in MSUD patients may be useful to develop therapeutic strategies to modulate the hyperinflammatory/hypoinflammatory axis.
Asunto(s)
Aminoácidos de Cadena Ramificada/administración & dosificación , Encéfalo/efectos de los fármacos , Citocinas/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Esquema de Medicación , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a severe deficiency in the activity of the branched-chain α-keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Infections have a significant role in precipitating acute metabolic decompensation in patients with MSUD; however, the mechanisms underlying the neurotoxicity in this disorder are poorly understood. In this study, we subjected rats to the coadministration of lipopolysaccharide (LPS), which is a major component of gram-negative bacteria cell walls, and high concentrations of BCAA (H-BCAA) to determine their effects on the permeability of the blood-brain barrier (BBB) and on the levels of matrix metalloproteinases (MMP-2 and MMP-9). Our results demonstrated that the coadministration of H-BCAA and LPS causes breakdown of the BBB and increases the levels of MMP-2 and MMP-9 in the hippocampus of these rats. On the other hand, examination of the cerebral cortex of the 10- and 30-day-old rats revealed a significant difference in Evan's Blue content after coadministration of H-BCAA and LPS, as MMP-9 levels only increased in the cerebral cortex of the 10-day-old rats. In conclusion, these results suggest that the inflammatory process associated with high levels of BCAA causes BBB breakdown. Thus, we suggest that BBB breakdown is relevant to the perpetuation of brain inflammation and may be related to the brain dysfunction observed in MSUD patients.
Asunto(s)
Aminoácidos de Cadena Ramificada/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Lipopolisacáridos/farmacología , Enfermedad de la Orina de Jarabe de Arce/tratamiento farmacológico , Metaloproteinasas de la Matriz/metabolismo , Aminoácidos de Cadena Ramificada/administración & dosificación , Aminoácidos de Cadena Ramificada/sangre , Animales , Barrera Hematoencefálica/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática , Hipocampo/efectos de los fármacos , Inflamación/tratamiento farmacológico , Lipopolisacáridos/administración & dosificación , Masculino , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Enfermedad de la Orina de Jarabe de Arce/patología , Ratas WistarRESUMEN
Sepsis is defined as the host's reaction to infection and characterised by a systemic inflammatory response with important clinical implications. Central nervous system dysfunction secondary to sepsis is associated with local generation of pro- and anti-inflammatory cytokines, impaired cerebral microcirculation, an imbalance of neurotransmitters, apoptosis and cognitive impairment. It's known that the IL-1ß is one of the first cytokines to be altered. Thus, the objective of this study was to evaluate the role of IL-1ß in cognitive parameters in brain tissue through the use of an IL-1ß (IL-1ra) receptor antagonist up to 10 days and to assess blood-brain barrier permeability, cytokine levels, oxidative parameters and energetic metabolism up to 24 h, after sepsis induction. To this aim, we used sham-operated Wistar rats or submitted to the cecal ligation and perforation (CLP) procedure. Immediately after, the animals received one dose of 10 µg of IL-1ra. After 24 h, the rats were killed and were evaluated for biochemical parameters in the pre-frontal cortex, hippocampus and striatum. After 10 days, the animals were submitted to the habituation to the open field and step-down inhibitory avoidance task. We observed that the use of IL-1ra reverted the increase of blood-brain barrier permeability in the pre-frontal cortex, hippocampus and striatum; the increase of IL-1ß, IL1-6 and TNF-α levels in the pre-frontal cortex and striatum; the decrease of complex I activity in the pre-frontal, hippocampus and striatum; the increase of oxidative parameters in pre-frontal cortex, hippocampus and striatum; and cognitive impairment. In conclusion, the results observed in this study reinforce the role of acute brain inflammatory response, in particular, the IL1ß response, in the cognitive impairment associated with sepsis.