RESUMEN
Mucopolysaccharidosis type II (MPS II) is a disorder caused by a deficient activity of iduronate-2-sulfatase, a lysosomal enzyme responsible for degrading glycosaminoglycans (GAGs). The abnormal storage of GAGs within lysosomes disrupts cellular homeostasis and leads to a severe symptomatology. Patients present neuropsychiatric impairment characterized by mental retardation and impaired cognition. The aim of this study was to quantify four neurodegeneration biomarkers in plasma: brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF-AA), neural cell adhesion molecule (NCAM) and cathepsin-D, as well as to identify possible correlations with urinary GAGs in seven patients undergoing treatment with ERT (Elaprase® 0.5 mg/kg of body weight). Patients with both severe and attenuated forms of MPS II showed signs of neurodegeneration in neuroimaging exams. Patients have a decrease in BDNF and PDGF-AA concentrations, and an increase in NCAM level compared to controls. No alterations in cathepsin-D concentration were seen. GAGs levels were higher in patients than in controls, but no significant correlations between GAGs and biomarkers were observed. These results evidence that patients have neurodegeneration and that monitoring these biomarkers might be useful for assessing this process. To this date, this is the first work to analyze these plasmatic markers of neurodegeneration in patients.
Asunto(s)
Mucopolisacaridosis II , Humanos , Mucopolisacaridosis II/complicaciones , Mucopolisacaridosis II/tratamiento farmacológico , Mucopolisacaridosis II/diagnóstico , Factor Neurotrófico Derivado del Encéfalo/uso terapéutico , Terapia de Reemplazo Enzimático , Glicosaminoglicanos/metabolismo , Glicosaminoglicanos/uso terapéutico , Biomarcadores , Moléculas de Adhesión de Célula Nerviosa/uso terapéuticoRESUMEN
Maple syrup urine disease (MSUD) is caused by a deficiency in the activity of the branched-chain α-ketoacid dehydrogenase (BCKD) complex, promoting the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their respective α-keto acids. MSUD is an autosomal recessive hereditary metabolic disorder characterized by ketoacidosis, ataxia, coma, and mental and psychomotor retardation. The mechanisms involved in the brain damage caused by MSUD are not fully understood. Early diagnosis and treatment, as well as proper control of metabolic decompensation crises, are crucial for patients' survival and for a better prognosis. The recommended treatment consists of a high-calorie diet with restricted protein intake and specific formulas containing essential amino acids, except those accumulated in MSUD. This treatment will be maintained throughout life, being adjusted according to the patients' nutritional needs and BCAA concentration. Because dietary treatment may not be sufficient to prevent neurological damage in MSUD patients, other therapeutic strategies have been studied, including liver transplantation. With transplantation, it is possible to obtain an increase of about 10% of the normal BCKD in the body, an amount sufficient to maintain amino acid homeostasis and reduce metabolic decompensation crises. However, the experience related to this practice is very limited when considering the shortage of liver for transplantation and the risks related to the surgical procedure and immunosuppression. Thus, the purpose of this review is to survey the benefits, risks, and challenges of liver transplantation in the treatment of MSUD.
Asunto(s)
Trasplante de Hígado , Enfermedad de la Orina de Jarabe de Arce , Humanos , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Aminoácidos de Cadena Ramificada , Leucina , DietaRESUMEN
Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L-carnitine (L-car) deficiency, compound that has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro- and anti-inflammatory cytokines, as well as the L-car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L-car levels in the patients under treatment. Inverse correlation between Phe versus L-car and nitrate plus nitrite versus L-car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)-1ß, interferons (IFN)-gamma, IL-2, tumor necrosis factor (TNF)-alpha, IL-8 and IL-6 in the patients at late diagnosis compared to controls, and IL-8 in the patients at early diagnosis and treatment compared to controls. Increased IL-2, TNF-alpha, IL-6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL-6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN-gamma and L-car in treated patients. Otherwise, it was observed that there were increased IL-4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8-isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro-oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L-car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.
Asunto(s)
Citocinas , Fenilcetonurias , Recién Nacido , Humanos , Fenilalanina , Diagnóstico Tardío , Interleucina-2 , Interleucina-6 , Interleucina-8 , Carnitina/farmacología , Fenilcetonurias/diagnóstico , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/orina , Factor de Necrosis Tumoral alfaRESUMEN
Lysosomal acid lipase deficiency (LALD) is an inborn error of metabolism that lacks satisfactory treatment, which leads to the development of severe hepatic and cardiac complications and may even lead to death. In this sense, knowledge of the mechanisms involved in the pathophysiology of this disorder becomes essential to allow the search for new therapeutic strategies. There are no studies in the literature investigating the role of reactive species and inflammatory processes in the pathophysiology of this disorder. Therefore, the aim of this work was to investigate parameters of oxidative and inflammatory stress in LALD patients. In this work, we obtained results that demonstrate that LALD patients are susceptible to oxidative stress caused by an increase in the production of free radicals, observed by the increase of 2-7-dihydrodichlorofluorescein. The decrease in sulfhydryl content reflects oxidative damage to proteins, as well as a decrease in antioxidant defenses. Likewise, the increase in urinary levels of di-tyrosine observed also demonstrates oxidative damage to proteins. Furthermore, the determination of chitotriosidase activity in the plasma of patients with LALD was significantly higher, suggesting a pro-inflammatory state. An increase in plasma oxysterol levels was observed in patients with LALD, indicating an important relationship between this disease and cholesterol metabolism and oxidative stress. Also, we observed in LALD patients increased levels of nitrate production. The positive correlation found between oxysterol levels and activity of chitotriosidase in these patients indicates a possible link between the production of reactive species and inflammation. In addition, an increase in lipid profile biomarkers such as total and low-density lipoprotein cholesterol were demonstrated in the patients, which reinforces the involvement of cholesterol metabolism. Thus, we can assume that, in LALD, oxidative and nitrosative damage, in addition to inflammatory process, play an important role in its evolution and future clinical manifestations. In this way, we can suggest that the study of the potential benefit of the use of antioxidant and anti-inflammatory substances as an adjuvant tool in the treatment will be important, which should be associated with the already recommended therapy.
Asunto(s)
Antioxidantes , Estrés Oxidativo , Humanos , Colesterol , Lípidos , Enfermedad de WolmanRESUMEN
Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.
Asunto(s)
Enfermedad de Niemann-Pick Tipo C , Humanos , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/metabolismo , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Daño del ADNRESUMEN
Although phenylalanine (Phe) is known to be neurotoxic in phenylketonuria (PKU), its exact pathogenetic mechanisms of brain damage are still poorly known. Furthermore, much less is known about the role of the Phe derivatives phenylacetic (PAA), phenyllactic (PLA) and phenylpyruvic (PPA) acids that also accumulate in this this disorder on PKU neuropathology. Previous in vitro and in vivo studies have shown that Phe elicits oxidative stress in brain of rodents and that this deleterious process also occurs in peripheral tissues of phenylketonuric patients. In the present study, we investigated whether Phe and its derivatives PAA, PLA and PPA separately or in combination could induce reactive oxygen species (ROS) formation and provoke DNA damage in C6 glial cells. We also tested the role of L-carnitine (L-car), which has been recently considered an antioxidant agent and easily cross the blood brain barrier on the alterations of C6 redox status provoked by Phe and its metabolites. We first observed that cell viability was not changed by Phe and its metabolites. Furthermore, Phe, PAA, PLA and PPA, at concentrations found in plasma of PKU patients, provoked marked DNA damage in the glial cells separately and when combined. Of note, these effects were totally prevented (Phe, PAA and PPA) or attenuated (PLA) by L-car pre-treatment. In addition, a potent ROS formation also induced by Phe and PAA, whereas only moderate increases of ROS were caused by PPA and PLA. Pre-treatment with L-car also prevented Phe- and PAA-induced ROS generation, but not that provoked by PLA and PPA. Thus, our data show that Phe and its major metabolites accumulated in PKU provoke extensive DNA damage in glial cells probably by ROS formation and that L-car may potentially represent an adjuvant therapeutic agent in PKU treatment.
Asunto(s)
Lesiones Encefálicas , Fenilcetonurias , Lesiones Encefálicas/tratamiento farmacológico , Carnitina/farmacología , Carnitina/uso terapéutico , Humanos , Cetoácidos/farmacología , Estrés Oxidativo , Fenilalanina/farmacología , Fenilalanina/uso terapéuticoRESUMEN
Glutaric aciduria type 1 (GA-1) is a rare but treatable inherited disease caused by deficiency of glutaryl-CoA dehydrogenase activity due to GCDH gene mutations. In this study, we report 24 symptomatic GA-1 Brazilian patients, and present their clinical, biochemical, and molecular findings. Patients were diagnosed by high levels of glutaric and/or 3-hydroxyglutaric and glutarylcarnitine. Diagnosis was confirmed by genetic analysis. Most patients had the early-onset severe form of the disease and the main features were neurological deterioration, seizures and dystonia, usually following an episode of metabolic decompensation. Despite the early symptomatology, diagnosis took a long time for most patients. We identified 13 variants in the GCDH gene, four of them were novel: c.91 + 5G > A, c.167T > G, c.257C > T, and c.10A > T. The most common mutation was c.1204C > T (p.R402W). Surprisingly, the second most frequent mutation was the new mutation c.91 + 5G > A (IVS1 ds G-A + 5). Our results allowed a complete characterization of the GA-1 Brazilian patients. Besides, they expand the mutational spectrum of GA-1, with the description of four new mutations. This work reinforces the importance of awareness of GA-1 among doctors in order to allow early diagnosis and treatment in countries like Brazil where the disease has not been included in newborn screening programs.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Encefalopatías Metabólicas/diagnóstico , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/genética , Mutación , Errores Innatos del Metabolismo de los Aminoácidos/genética , Encefalopatías Metabólicas/genética , Brasil , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/sangre , Encefalopatías Metabólicas/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Catepsina D/sangre , Glutaril-CoA Deshidrogenasa/deficiencia , Degeneración Nerviosa/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Biomarcadores/sangre , Encefalopatías Metabólicas/complicaciones , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/sangre , Humanos , Lactante , Recién Nacido , Masculino , Degeneración Nerviosa/sangre , Degeneración Nerviosa/etiología , Moléculas de Adhesión de Célula Nerviosa/sangre , Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo ß-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-L-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1ß) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.
Asunto(s)
Acetilcisteína/farmacología , Cromanos/farmacología , Ácidos Grasos/farmacología , Inflamación/patología , Neuroglía/patología , Estrés Nitrosativo , Estrés Oxidativo , Rosuvastatina Cálcica/farmacología , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Supervivencia Celular/efectos de los fármacos , Vesículas Citoplasmáticas/metabolismo , Daño del ADN , Interleucina-1beta/metabolismo , Isoprostanos/metabolismo , Neuroglía/metabolismo , Fármacos Neuroprotectores/farmacología , Nitratos/metabolismo , Nitritos/metabolismo , Estrés Nitrosativo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
The deficiency of the enzyme glutaryl-CoA dehydrogenase, known as glutaric acidemia type I (GA-I), leads to the accumulation of glutaric acid (GA) and glutarilcarnitine (C5DC) in the tissues and body fluids, unleashing important neurotoxic effects. l-carnitine (l-car) is recommended for the treatment of GA-I, aiming to induce the excretion of toxic metabolites. l-car has also demonstrated an important role as antioxidant and anti-inflammatory in some neurometabolic diseases. This study evaluated GA-I patients at diagnosis moment and treated the oxidative damage to lipids, proteins, and the inflammatory profile, as well as in vivo and in vitro DNA damage, reactive nitrogen species (RNS), and antioxidant capacity, verifying if the actual treatment with l-car (100 mg kg-1 day-1 ) is able to protect the organism against these processes. Significant increases of GA and C5DC were observed in GA-I patients. A deficiency of carnitine in patients before the supplementation was found. GA-I patients presented significantly increased levels of isoprostanes, di-tyrosine, urinary oxidized guanine species, and the RNS, as well as a reduced antioxidant capacity. The l-car supplementation induced beneficial effects reducing these biomarkers levels and increasing the antioxidant capacity. GA, in three different concentrations, significantly induced DNA damage in vitro, and the l-car was able to prevent this damage. Significant increases of pro-inflammatory cytokines IL-6, IL-8, GM-CSF, and TNF-α were shown in patients. Thus, the beneficial effects of l-car presented in the treatment of GA-I are due not only by increasing the excretion of accumulated toxic metabolites, but also by preventing oxidative damage.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas/metabolismo , Carnitina/farmacología , Daño del ADN , Glutaril-CoA Deshidrogenasa/deficiencia , Estrés Oxidativo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Carnitina/uso terapéutico , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/efectos de los fármacos , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Lactante , Masculino , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Especies de Nitrógeno ReactivoRESUMEN
Maple syrup urine disease (MSUD), or branched-chain α-keto aciduria, is an inherited disorder that is caused by a deficiency in branched-chain α-keto acid dehydrogenase complex (BCKAD) activity. Blockade of this pathway leads to the accumulation of the branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, and their respective ketoacids in tissues. The main clinical symptoms presented by MSUD patients include ketoacidosis, hypoglycemia, opisthotonos, poor feeding, apnea, ataxia, convulsions, coma, psychomotor delay, and mental retardation. Although increasing evidence indicates that oxidative stress is involved in the pathophysiology of this disease, the mechanisms of the brain damage caused by this disorder remain poorly understood. In the present study, we investigated the effect of BCAAs on some oxidative stress parameters and evaluated the efficacy of L-carnitine (L-car), an efficient antioxidant that may be involved in the reduction of oxidative damage observed in some inherited neurometabolic diseases, against these possible pro-oxidant effects of a chronic MSUD model in the cerebral cortex and cerebellum of rats. Our results showed that chronic BCAA administration was able to promote both lipid and protein oxidation, impair brain antioxidant defenses, and increase reactive species production, particularly in the cerebral cortex, and that L-car was able to prevent these effects. Taken together, the present data indicate that chronic BCAA administration significantly increased oxidative damage in the brains of rats subjected to a chronic model of MSUD and that L-car may be an efficient antioxidant in this disorder.
Asunto(s)
Encéfalo/patología , Carnitina/farmacología , Enfermedad de la Orina de Jarabe de Arce/inducido químicamente , Enfermedad de la Orina de Jarabe de Arce/patología , Estrés Oxidativo/efectos de los fármacos , Aminoácidos de Cadena Ramificada/farmacología , Animales , Catalasa/metabolismo , Modelos Animales de Enfermedad , Glutatión/metabolismo , Modelos Biológicos , Carbonilación Proteica/efectos de los fármacos , Ratas Wistar , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acids (BCAA). The defect in the branched-chain α-keto acid dehydrogenase complex activity leads to an accumulation of these compounds and their corresponding α-keto-acids and α-hydroxy-acids. Studies have shown that oxidative stress may be involved in neuropathology of MSUD. L-carnitine (L-car), which has demonstrated an important role as antioxidant by reducing and scavenging free radicals formation and by enhancing the activity of antioxidant enzymes, have been used in the treatment of some metabolic rare disorders. This study evaluated the oxidative stress parameters, di-tyrosine, isoprostanes and antioxidant capacity, in urine of MSUD patients under protein-restricted diet supplemented or not with L-car capsules at a dose of 50 mg kg(-1) day(-1). It was also determined urinary α-keto isocaproic acid levels as well as blood free L-car concentrations in blood. It was found a deficiency of carnitine in patients before the L-car supplementation. Significant increases of di-tyrosine and isoprostanes, as well as reduced antioxidant capacity, were observed before the treatment with L-car. The L-car supplementation induced beneficial effects on these parameters reducing the di-tyrosine and isoprostanes levels and increasing the antioxidant capacity. It was also showed a significant increase in urinary of α-ketoisocaproic acid after 2 months of L-car treatment, compared to control group. In conclusion, our results suggest that L-car may have beneficial effects in the treatment of MSUD by preventing oxidative damage to the cells and that urine can be used to monitorize oxidative damage in patients affected by this disease.
Asunto(s)
Biomarcadores/orina , Suplementos Dietéticos , Enfermedad de la Orina de Jarabe de Arce/orina , Aminoácidos/orina , Análisis de Varianza , Antioxidantes/metabolismo , Niño , Preescolar , Dinoprost/análogos & derivados , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Isoprostanos/orina , Cetoácidos/orina , Masculino , Enfermedad de la Orina de Jarabe de Arce/dietoterapia , Espectrometría de Masas en Tándem , Tirosina/orinaRESUMEN
There is increasing evidence suggesting that oxidative stress plays an important role in the development of many chronic and degenerative conditions such as diabetic encephalopathy and depression. Considering that diabetic rats and mice present higher depressive-like behaviour when submitted to the forced swimming test and that treatment with insulin and/or clonazepam is able to reverse the behavioural changes of the diabetic rats, the present work investigated the antioxidant status, specifically total antioxidant reactivity and antioxidant potential of insulin and clonazepam, as well as the effect of this drugs upon protein oxidative damage and reactive species formation in cortex, hippocampus and striatum from diabetic rats submitted to forced swimming test. It was verified that longer immobility time in diabetic rats and insulin plus clonazepam treatment reversed this depressive-like behaviour. Moreover, data obtained in this study allowed to demonstrate through different parameters such as protein carbonyl content, 2'7'-dichlorofluorescein oxidation, catalase, superoxide dismutase, glutathione peroxidase assay, total radical-trapping antioxidant potential and total antioxidant reactivity that there is oxidative stress in cortex, hippocampus and striatum from diabetic rats under depressive-like behaviour and highlight the insulin and/or clonazepam effect in these different brain areas, restoring antioxidant status and protein damage.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Encefalopatías/complicaciones , Clonazepam/uso terapéutico , Depresión/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Animales , Antioxidantes/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Depresión/etiología , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Maple syrup urine disease (MSUD) is an inborn error of metabolism biochemically characterized by elevated levels of the branched chain amino acids (BCAA) leucine, isoleucine, valine and the corresponding branched-chain α-keto acids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. l-Carnitine (l-Car) plays a central role in the cellular energy metabolism because it transports long-chain fatty acids for oxidation and ATP generation. In recent years many studies have demonstrated the antioxidant role of this compound. In this work, we investigated the effect of BCAA-restricted diet supplemented or not with l-Car on lipid peroxidation and in protein oxidation in MSUD patients. We found a significant increase of malondialdehyde and of carbonyl content in plasma of MSUD patients under BCAA-restricted diet compared to controls. Furthermore, patients under BCAA-restricted diet plus l-Car supplementation presented a marked reduction of malondialdehyde content in relation to controls, reducing the lipid peroxidation. In addition, free l-Car concentrations were negatively correlated with malondialdehyde levels. Our data show that l-Car may have an antioxidant effect, protecting against the lipid peroxidation and this could represent an additional therapeutic approach to the patients affected by MSUD.
Asunto(s)
Carnitina/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedad de la Orina de Jarabe de Arce/tratamiento farmacológico , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Proteínas/metabolismo , Complejo Vitamínico B/uso terapéutico , Aminoácidos/metabolismo , Análisis de Varianza , Niño , Preescolar , Femenino , Humanos , Masculino , Malondialdehído/metabolismo , Carbonilación Proteica/efectos de los fármacosRESUMEN
Paints are composed of an extensive variety of hazardous substances, such as organic solvents and heavy metals. Biomonitoring is an essential tool for assessing the risk to occupational health. Thus, this study analyzed the levels of biomarkers of exposure for toluene, xylene, styrene, ethylbenzene, and lead, as well as the oxidative stress biomarker alterations in painters of an industry. Lipid peroxidation biomarker (MDA), delta-aminolevulinate dehydratase (ALA-D), nonprotein thyol groups, superoxide dismutase and catalase (CAT) were analyzed in exposed and nonexposed subjects. We estimated which of the paint constituents have the greatest influence on the changes in the biomarkers of oxidative stress in this case of co-exposure. The results demonstrated that despite the fact that all the biomarkers of exposure were below the biological exposure limits, the MDA levels and antioxidant enzyme activities were increased, while nonprotein thyol groups and ALA-D levels were decreased in painters when compared with nonexposed subjects. After statistic test, toluene could be suggested as the principal factor responsible for increased lipid peroxidation and inhibition of ALA-D enzyme; however, further studies on the inhibition of ALA-D enzyme by toluene are necessary.