RESUMEN
BACKGROUND: In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition. OBJECTIVE: This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis. METHODS: Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days. RESULTS: Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified. CONCLUSION: In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.
RESUMEN
AIMS: Infection is a complication after stroke and outcomes vary by sex. Thus, we investigated if sepsis affects brain from ischemic stroke and sex involvement. MAIN METHODS: Male and female Wistar rats, were submitted to middle cerebral artery occlusion (MCAO) and after 7 days sepsis to cecal ligation and perforation (CLP). Infarct size, neuroinflammation, oxidative stress, and mitochondrial activity were quantified 24 h after CLP in the prefrontal cortex and hippocampus. Survival and neurological score were assessed up to 15 days after MCAO or 8 days after CLP (starting at 2 h after MCAO) and memory at the end. KEY FINDINGS: CLP decreased survival, increased neurological impairments in MCAO females. Early, in male sepsis following MCAO led to increased glial activation in the brain structures, and increased TNF-α and IL-1ß in the hippocampus. All groups had higher IL-6 in both tissues, but the hippocampus had lower IL-10. CLP potentiated myeloperoxidase (MPO) in the prefrontal cortex of MCAO male and female. In MCAO+CLP, only male increased MPO and nitrite/nitrate in hippocampus. Males in all groups had protein oxidation in the prefrontal cortex, but only MCAO+CLP in the hippocampus. Catalase decreased in the prefrontal cortex and hippocampus of all males and females, and MCAO+CLP only increased this activity in males. Female MCAO+CLP had higher prefrontal cortex complex activity than males. In MCAO+CLP-induced long-term memory impairment only in females. SIGNIFICANCE: The parameters evaluated for early sepsis after ischemic stroke show a worse outcome for males, while females are affected during long-term follow-up.
Asunto(s)
Accidente Cerebrovascular Isquémico , Ratas Wistar , Sepsis , Caracteres Sexuales , Animales , Masculino , Femenino , Sepsis/complicaciones , Sepsis/metabolismo , Ratas , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/patología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Estrés Oxidativo , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Recuperación de la Función , Factores Sexuales , Isquemia Encefálica/metabolismo , Isquemia Encefálica/complicaciones , Peroxidasa/metabolismoRESUMEN
Obesity causes inflammation in the adipose tissue and can affect the central nervous system, leading to oxidative stress and mitochondrial dysfunction. Therefore, it becomes necessary to seek new therapeutic alternatives. Gold nanoparticles (GNPs) could take carnitine to the adipose tissue, thus increasing fatty acid oxidation, reducing inflammation, and, consequently, restoring brain homeostasis. The objective of this study was to investigate the effects of GNPs associated with carnitine on the neurochemical parameters of obesity-induced mice. Eighty male Swiss mice that received a normal lipid diet (control group) or a high-fat diet (obese group) for 10 weeks were used. At the end of the sixth week, the groups were divided for daily treatment with saline, GNPs (70 µg/kg), carnitine (500 mg/kg), or GNPs associated with carnitine, respectively. Body weight was monitored weekly. At the end of the tenth week, the animals were euthanized and the mesenteric fat removed and weighed; the brain structures were separated for biochemical analysis. It was found that obesity caused oxidative damage and mitochondrial dysfunction in brain structures. Treatment with GNPs isolated reduced oxidative stress in the hippocampus. Carnitine isolated decreased the accumulation of mesenteric fat and oxidative stress in the hippocampus. The combination of treatments reduced the accumulation of mesenteric fat and mitochondrial dysfunction in the striatum. Therefore, these treatments in isolation, become a promising option for the treatment of obesity.
Asunto(s)
Encéfalo , Carnitina , Modelos Animales de Enfermedad , Oro , Nanopartículas del Metal , Obesidad , Estrés Oxidativo , Animales , Carnitina/farmacología , Carnitina/administración & dosificación , Carnitina/uso terapéutico , Oro/farmacología , Masculino , Obesidad/tratamiento farmacológico , Obesidad/patología , Obesidad/complicaciones , Ratones , Estrés Oxidativo/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Dieta Alta en Grasa , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/patología , Lesiones Encefálicas/metabolismo , Peso Corporal/efectos de los fármacosRESUMEN
Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Ratas , Animales , Enfermedad de la Orina de Jarabe de Arce/tratamiento farmacológico , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Memantina/farmacología , Memantina/uso terapéutico , Acetilcolinesterasa , Modelos Animales de Enfermedad , Aminoácidos de Cadena Ramificada , Antioxidantes/farmacología , InflamaciónRESUMEN
This study aimed to evaluate the behavioral and energy metabolism parameters in female mice subjected to obesity and offspring deprivation (OD) stress. Eighty female Swiss mice, 40 days old, were weighed and divided into two groups: Control group (control diet, n = 40) and Obese group (high-fat diet, n = 40), for induction of the animal model of obesity, the protocol was based on the consumption of a high-fat diet and lasted 8 weeks. Subsequently, the females were subjected to pregnancy, after the birth of the offspring, were divided again into the following groups (n = 20): Control non-deprived (ND), Control + OD, Obese ND, and Obese + OD, for induction of the stress protocol by OD. After the offspring were 21 days old, weaning was performed and the dams were subjected to behavioral tests. The animals were humanely sacrificed, the brain was removed, and brain structures were isolated to assess energy metabolism. Both obesity and OD led to anhedonia in the dams. It was shown that the structures most affected by obesity and OD are the hypothalamus and hippocampus, as evidenced by the mitochondrial dysfunction found in these structures. When analyzing the groups separately, it was observed that OD led to more pronounced mitochondrial damage; however, the association of obesity with OD, as well as obesity alone, also generated damage. Thus, it is concluded that obesity and OD lead to anhedonia in animals and to mitochondrial dysfunction in the hypothalamus and hippocampus, which may lead to losses in feeding control and cognition of the dams.
Asunto(s)
Anhedonia , Efectos Tardíos de la Exposición Prenatal , Embarazo , Ratones , Femenino , Animales , Humanos , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Destete , Metabolismo EnergéticoRESUMEN
Maple syrup urine disease (MSUD) is an inherited metabolic disorder caused by a deficiency in branched-chain alpha-ketoacid dehydrogenase complex (BCKAC). The treatment is a standard therapy based on a protein-restricted diet with low branched-chain amino acids (BCAA) content to reduce plasma levels and, consequently, the effects of accumulating their metabolites, mainly in the central nervous system. Although the benefits of dietary therapy for MSUD are undeniable, natural protein restriction may increase the risk of nutritional deficiencies, resulting in a low total antioxidant status that can predispose and contribute to oxidative stress. As MSUD is related to redox and energy imbalance, melatonin can be an important adjuvant treatment. Melatonin directly scavenges the hydroxy radical, peroxyl radical, nitrite anion, and singlet oxygen and indirectly induces antioxidant enzyme production. Therefore, this study assesses the role of melatonin treatment on oxidative stress in brain tissue and behavior parameters of zebrafish (Danio rerio) exposed to two concentrations of leucine-induced MSUD: leucine 2 mM and 5mM; and treated with 100 nM of melatonin. Oxidative stress was assessed through oxidative damage (TBARS, DCF, and sulfhydryl content) and antioxidant enzyme activity (SOD and CAT). Melatonin treatment improved redox imbalance with reduced TBARS levels, increased SOD activity, and normalized CAT activity to baseline. Behavior was analyzed with novel object recognition test. Animals exposed to leucine improved object recognition due to melatonin treatment. With the above, we can suggest that melatonin supplementation can protect neurologic oxidative stress, protecting leucine-induced behavior alterations such as memory impairment.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Melatonina , Animales , Leucina/efectos adversos , Leucina/metabolismo , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Pez Cebra/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Melatonina/farmacología , Melatonina/uso terapéutico , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Estrés Oxidativo , Aminoácidos de Cadena Ramificada/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Maple Syrup Urine Disease (MSUD) is an autosomal recessive inborn error of metabolism (IEM), responsible for the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, in addition to their α-keto acids α-ketoisocaproic acid (KIC), α-keto-ß-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) in the plasma and urine of patients. This process occurs due to a partial or total blockage of the dehydrogenase enzyme activity of branched-chain α-keto acids. Oxidative stress and inflammation are conditions commonly observed on IEM, and the inflammatory response may play an essential role in the pathophysiology of MSUD. We aimed to investigate the acute effect of intracerebroventricular (ICV) administration of KIC on inflammatory parameters in young Wistar rats. For this, sixteen 30-day-old male Wistar rats receive ICV microinjection with 8 µmol KIC. Sixty minutes later, the animals were euthanized, and the cerebral cortex, hippocampus, and striatum structures were collected to assess the levels of pro-inflammatory cytokines (INF-γ; TNF-α, IL-1ß). The acute ICV administration of KIC increased INF-γ levels in the cerebral cortex and reduced the levels of INF-γ and TNF-α in the hippocampus. There was no difference in IL-1ß levels. KIC was related to changes in the levels of pro-inflammatory cytokines in the brain of rats. However, the inflammatory mechanisms involved in MSUD are poorly understood. Thus, studies that aim to unravel the neuroinflammation in this pathology are essential to understand the pathophysiology of this IEM.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Factor de Necrosis Tumoral alfa , Ratas , Animales , Masculino , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Estrés Oxidativo , Cetoácidos/farmacología , Enfermedad de la Orina de Jarabe de Arce/tratamiento farmacológico , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Aminoácidos de Cadena Ramificada/metabolismoRESUMEN
Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism (EIM) biochemically characterized by the tissue accumulation of branched-chain amino acids (BCAA) and their branched-chain alpha-keto acids. The mechanisms by which BCAA and their branched-chain alpha-keto acids lead to the neurological damage observed in MSUD are poorly understood. Mounting evidence has demonstrated that BCAA induce the overproduction of reactive oxygen species, which may modulate several important signaling pathways necessary for cellular homeostasis maintenance, such as autophagy. Taking this into account, we evaluated the effects of BCAA on the autophagic pathway in brain structures of rats submitted to the administration of these amino acids (animal model of MSUD). Our findings showed that BCAA significantly increased the levels of Beclin-1, ATG7, and ATG5 in the cerebral cortex of rats. In addition, BCAA augmented ATG12 levels in the striatum and ATG5 and LC3 I-II in the hippocampus. Therefore, our work demonstrates that the administration of BCAA increases autophagy and autophagic cell death, possibly mediated by the elevated levels of reactive species generated by BCAA.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Ratas , Animales , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Ratas Wistar , Modelos Animales de Enfermedad , Encéfalo/metabolismo , Cetoácidos , AutofagiaRESUMEN
Maple Syrup Urine Disease (MSUD) is a metabolic disorder characterized by high levels in blood and urine of branched-chain amino acids leucine, isoleucine, and valine and their alpha-ketoacids, by a partial or total blockade in the activity of branched-chain complex alpha-keto acids dehydrogenase. The main symptoms in MSUD occur in the central nervous system, including cognitive deficits, locomotor, poor feeding, seizures, psychomotor delay, and mental retardation, but the mechanisms of neurotoxicity and behavior alteration due to this disease are poorly understood, thus this study aimed at showing the effects of leucine exposure on glutamate levels and behavior in zebrafish. For this, we analyzed the behavior using the social preference test and novel object recognition test, moreover, we analyse the glutamate levels and uptake using scintillation and high-performance liquid chromatography methods. Our results demonstrated a decrease in glutamate levels and uptake, accompanied by memory and social impairment. In conclusion, these results suggest that alterations in glutamate levels can be associated with behavior impairment, however, more studies are necessary to understand the mechanisms for brain damage in MSUD.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Pez Cebra , Animales , Leucina , Ácido Glutámico , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Aminoácidos de Cadena Ramificada/farmacologíaRESUMEN
Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Tiazepinas , Aminoácidos de Cadena Ramificada/metabolismo , Animales , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Ratas , Ratas Wistar , Tiazepinas/farmacologíaRESUMEN
Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder caused by a deficiency in the activity of the branched-chain alpha-ketoacid dehydrogenase complex leading to the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, and valine and their respective branched-chain α-ketoacids and corresponding hydroxy acids. Considering that Danio rerio, known as zebrafish, has been widely used as an experimental model in several research areas because it has favorable characteristics that complement other experimental models, this study aimed to evaluate oxidative stress parameters in zebrafish exposed to high levels of leucine (2 mM and 5 mM), in a model similar of MSUD. Twenty-four hours after exposure, the animals were euthanized, and the brain content dissected for analysis of oxidative stress parameters: thiobarbituric acid reactive substances (TBARS), 2',7'-dichlorofluorescein oxidation assay (DCF); content of sulfhydryl, and superoxide dismutase (SOD) and catalase (CAT) activities. Animals exposed to 2 mM and 5 mM leucine showed an increase in the measurement of TBARS and decreased sulfhydryl content. There were no significant changes in DCF oxidation. In addition, animals exposed to 2 mM and 5 mM leucine were found to have decreased SOD activity and increased CAT activity. Based on these results, exposure of zebrafish to high doses of leucine can act as a promising animal model for MSUD, providing a better understanding of the toxicity profile of leucine exposure and its use in future investigations and strategies related to the pathophysiology of MSUD.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Pez Cebra , Animales , Antioxidantes/farmacología , Encéfalo/metabolismo , Leucina/metabolismo , Leucina/farmacología , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Estrés Oxidativo , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Pez Cebra/metabolismoRESUMEN
Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder that affects the activity of the branched-chainα-keto acid dehydrogenase complex (BCDK). This deficiency on BCDK complex results in the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine, and their corresponding α-keto acids. Epigenetic changes can negatively affect the metabolism of BCAA. These changes are catalyzed by the epigenetic regulatory enzymes, e.g., DNA methyltransferase (DNMT), histone deacetylases (HDAC), and histone acetyltransferases (HAT). However, the impacts of BCAA administration on the activity of epigenetic regulatory enzymes in the brain of MSUD patients are still unknown. In this study, we aimed to demonstrate the impact of BCAA administration on the activity of DNMT, HDAC, and HAT in the brain structures of infant rats, an animal model of MSUD. For that, we administered a BCAA pool to infant rats for 21 days. We demonstrated that BCAA administration significantly increased the DNMT and HDAC activities in the hippocampus and striatum, but not in the cerebral cortex of MSUD infant rats. A positive correlation was observed between HDAC and DNMT activities in the hippocampus and striatum of animals exposed to BCAA injections. Our results showed that the BCAA administration could modulate epigenetic regulatory enzymes, mainly DNMT and HDAC, in the brains of infant rats. Therefore, we suggest that the increase in the activity of DNMT and HDAC in the hippocampus and striatum could partially explain the neurological impairments presented in animal models of MSUD.
Asunto(s)
Aminoácidos de Cadena Ramificada/administración & dosificación , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Hipocampo/efectos de los fármacos , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
Maple syrup urine disease (MSUD) is characterized by a deficiency in the mitochondrial branched-chain α-keto acid dehydrogenase complex activity and, consequently, accumulation of the branched-chain amino acids and their respective branched-chain α-keto acids in fluids and the tissue. MSUD clinical symptoms include neurological alterations. KIC is considered one of the significant neurotoxic metabolites since its increased plasma concentrations are associated with neurological symptoms. We evaluated the effect of KIC intracerebroventricular (ICV) injection in hippocampal mitochondria function in rats. We also investigated the impact of KIC in cells' metabolic activity (using MTT assay) and reactive species (RS) production in HT-22 cells. For this, thirty-day-old male rats were bilaterally ICV injected with KIC or aCSF. Thus, 1 hour after the administration, animals were euthanized, and the hippocampus was harvested for measured the activities of mitochondrial respiratory chain enzymes and RS production. Furthermore, HT-22 cells were incubated with KIC (1-10 mM) in 6, 12, and 24 h. Mitochondrial complexes activities were reduced, and the formation of RS was increased in the hippocampus of rats after KIC administration. Moreover, KIC reduced the cells' metabolic ability to reduce MTT and increased RS production in hippocampal neurons. Impairment in hippocampal mitochondrial function seems to be involved in the neurotoxicity induced by KIC.
Asunto(s)
Aminoácidos de Cadena Ramificada/metabolismo , Hipocampo/efectos de los fármacos , Cetoácidos/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Línea Celular , Hipocampo/metabolismo , Masculino , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Ratones , Ratas , Ratas WistarRESUMEN
Sepsis survivors present acute and long-term cognitive impairment and the pathophysiology of neurological dysfunction in sepsis involves microglial activation. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes have been demonstrated to perpetuate neuroinflammation. Thus, we investigated the involvement of the NLRP3 inflammasome activation on early and late brain changes in experimental sepsis. Two-month-old male Wistar rats were submitted to the sepsis model by cecal ligation and perforation (CLP group) or laparotomy only (sham group). Immediately after surgery, the animals received saline or NLRP3 inflammasome formation inhibitor (MCC950, 140 ng/kg) intracerebroventricularly. Prefrontal cortex and hippocampus were isolated for cytokine analysis, microglial and astrocyte activation, oxidative stress measurements, nitric oxide formation, and mitochondrial respiratory chain activity at 24 h after CLP. A subset of animals was followed for 10 days for survival assessment, and then behavioral tests were performed. The administration of MCC950 restored the elevation of IL-1ß, TNF-α, IL-6, and IL-10 cytokine levels in the hippocampus. NLRP3 receptor levels increased in the prefrontal cortex and hippocampus at 24 h after sepsis, associated with microglial, but not astrocyte, activation. MCC950 reduced oxidative damage to lipids and proteins as well as preserved the activity of the enzyme SOD in the hippocampus. Mitochondrial respiratory chain activity presented variations in both structures studied. MCC950 reduced microglial activation, decreased acute neurochemical and behavioral alteration, and increased survival after experimental sepsis.
Asunto(s)
Encéfalo/patología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sepsis/complicaciones , Enfermedad Aguda , Animales , Astrocitos/metabolismo , Encéfalo/metabolismo , Catalasa/metabolismo , Citocinas/metabolismo , Transporte de Electrón , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/metabolismo , Mediadores de Inflamación/metabolismo , Estimación de Kaplan-Meier , Peroxidación de Lípido , Masculino , Memoria , Trastornos de la Memoria/fisiopatología , Microglía/metabolismo , Mitocondrias/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Estrés Oxidativo , Corteza Prefrontal/metabolismo , Carbonilación Proteica , Ratas Wistar , Superóxido Dismutasa/metabolismo , Análisis de SupervivenciaRESUMEN
Autistic spectrum disorder (ASD) is a group of early-onset neurodevelopmental disorders characterized by impaired social and communication skills. Autism is widely described as a behavioral syndrome with multiple etiologies where may exhibit neurobiological, genetic, and psychological deficits. Studies have indicated that long term use of antibiotics can alter the intestinal flora followed by neuroendocrine changes, leading to behavioral changes. Indeed, previous studies demonstrate that a high dose of amoxicillin can change behavioral parameters in murine animal models. The objective was to evaluate behavioral and oxidative stress parameters in zebrafish exposed to a high dose of amoxicillin for 7 days. Young zebrafish were exposed to a daily concentration of amoxicillin (100 mg/L) for 7 days. Subsequently, the behavioral analysis was performed, and the brain content was dissected for the evaluation of oxidative stress parameters. Zebrafish exposed to a high dose of amoxicillin showed locomotor alteration and decreased social interaction behavior. In addition, besides the significant decrease of sulfhydryl content, there was a marked decrease in catalase activity, as well as an increased superoxide dismutase activity in brain tissue. Thus, through the zebrafish model was possible to note a central effect related to the exposition of amoxicillin, the same as observed in murine models. Further, the present data reinforce the relation of the gut-brain-axis and the use of zebrafish as a useful tool to investigate new therapies for autistic traits.
Asunto(s)
Amoxicilina/toxicidad , Antibacterianos/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Interacción Social/efectos de los fármacos , Factores de Edad , Amoxicilina/administración & dosificación , Animales , Antibacterianos/administración & dosificación , Relación Dosis-Respuesta a Droga , Peroxidación de Lípido/fisiología , Estrés Oxidativo/fisiología , Pez CebraRESUMEN
Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of branched α-ketoacid dehydrogenase complex (BCKDC) activity. Branched-chain amino acids (BCAA) accumulation is, at least in part, responsible for neurological disturbances characteristic of this metabolic disorder. Experimental studies demonstrated that high levels of BCAA induce brain oxidative stress. Considering that many antioxidants are obtained from the diet, the dietary restriction in MSUD patients probably produce deficiency of vitamins and micronutrients involved in antioxidant defenses. Supplementation with synthetic melatonin has been used to prevention and treatment of pathological conditions, including brain diseases. In this study, we aimed at investigating the potential neuroprotective effect of melatonin treatment in a MSUD experimental model. Infant rats (7 day old) received twice daily subcutaneous injections of a BCAA pool (0.21472 g/kg, 190 mmol/L leucine, 59 mmol/L isoleucine and 69 mmol/L valine in saline solution (15.8 µL/g per weight/injection) or saline alone, and supplemented with melatonin (10 mg/kg, intraperitoneal) for 21 days. Oxidative stress parameters, i.e. antioxidant enzyme activity, reactive species production and damage to lipids and proteins, were assessed in the cerebral cortex, hippocampus and striatum at twenty-eight days of age. In addition, the damage to blood cell DNA was evaluated. The chronic administration of BCAA pool in infant rats induced significant oxidative stress (p < 0.05) - such as oxidation of lipids and proteins, imbalance in antioxidant enzymes activities - damages in DNA (p < 0.05) and in brain structures (cerebral cortex, hippocampus and striatum). Notably, melatonin supplementation was able to ameliorate the oxidative (p < 0.05) and antioxidant (p < 0.05) parameters in the brain and blood of the rat model of MSUD. Our results show that melatonin could be a promising therapeutic agent for MSUD.
Asunto(s)
Aminoácidos de Cadena Ramificada/toxicidad , Antioxidantes/uso terapéutico , Daño del ADN/efectos de los fármacos , Enfermedad de la Orina de Jarabe de Arce/tratamiento farmacológico , Melatonina/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Daño del ADN/fisiología , Masculino , Enfermedad de la Orina de Jarabe de Arce/inducido químicamente , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Melatonina/farmacología , Estrés Oxidativo/fisiología , Ratas , Ratas WistarRESUMEN
O objetivo do estudo foi analisar os determinantes da satisfação do usuário com Diabetes Mellitus (DM) sobre o atendimento no ambulatório de especialidades de um Centro de Saúde Escola. O estudo transversal com abordagem qualitativa foi desenvolvido no ambulatório de especialidades com 20 usuários com diagnóstico de DM. Foram aplicadas entrevistas semiestruturadas por meio de um roteiro norteador. Utilizou-se software Atlas ti 7.0 para auxílio na codificação das falas e técnica de Análise de Conteúdo para análise dos dados. Como resultado, observou-se que os temas mais evidenciados estão relacionados à acessibilidade organizacional e à relação entre usuário, equipe e serviço na perspectiva da longitudinalidade. Observou-se a identificação do ambulatório de especialidade como fonte regular de cuidado e a insatisfação no que se refere à acessibilidade ao serviço...
The objective of the study was analyze user satisfaction determinants of patients with Diabetes Mellitus (DM) regarding the outpatient clinic specialties at the Health Centre of the School. Qualitative crosssectional study was carried out in outpatient specialty with 20 users with diagnosis of DM. We adopted the method of semi-structured interview using a scripting guide. We used Atlas it software 7.0 to aid in the decoding of speech, and analyzed it by content analysis. The empirical material encoded enabled to observe that the most evident themes are related to organizational accessibility and the relationship between user and service staff in perspective of longitudinality. It was observed the outpatient identifying clinic specialties as a regular source of care and dissatisfaction with regard to service accessibility...
Asunto(s)
Investigación sobre Servicios de Salud , Diabetes Mellitus , Satisfacción del PacienteRESUMEN
Este estudo descreve o repertório comportamental de 14 crianças com diagnóstico de câncer, com idade entre 4 e 12 anos, durante um procedimento de punção venosa para quimioterapia, assim como o de seus acompanhantes e auxiliares de enfermagem. A coleta de dados foi realizada mediante observação direta com auxílio da Observation Scale of Behavior Distress. Foram utilizados três sistemas de categorias de comportamento (para as crianças, os acompanhantes e os auxiliares de enfermagem). Não foram observadas diferenças significativas entre comportamentos concorrentes e não concorrentes de crianças pré-escolares e escolares. Observou-se maior variabilidade comportamental entre acompanhantes de pré-escolares e maior frequência de comportamentos verbais dirigidos a escolares em auxiliares de enfermagem. Discute-se a necessidade da preparação psicológica para procedimentos invasivos em oncologia pediátrica.
This study describes the behavioral repertoire of fourteen children, aged 4-12 years old, with cancer diagnoses, during a venepuncture procedure for chemotherapy, and of their caregivers and nursing assistants. Data collection was accomplished through direct observation with the use of the Observation Scale of Behavior Distress. Three systems of behavior categories were used (for children, caregivers and nursing assistants). There were no significant differences between concurrent and non-concurrent behaviors of preschool and school children. There was greater behavioral variability among caregivers of pre-school children and higher frequency of verbal behaviors directed to school children among nursing assistants. It is discussed the need of psychological preparation for invasive procedures in pediatric oncology.