Vannessa Gonçalves Araujo Lobato

Universidade Federal do Rio Grande do Sul, Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil

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Publications (4)7.19 Total impact

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    ABSTRACT: Zellweger syndrome (ZS) and some peroxisomal diseases are severe inherited disorders mainly characterized by neurological symptoms and cerebellum abnormalities, whose pathogenesis is poorly understood. Biochemically, these diseases are mainly characterized by accumulation of pristanic acid (Prist) and other fatty acids in the brain and other tissues. In this work, we evaluated the in vitro influence of Prist on redox homeostasis by measuring lipid, protein, and DNA damage, as well as the antioxidant defenses and the activities of aconitase and α-ketoglutarate dehydrogenase in cerebellum of 30-day-old rats. The effect of Prist on DNA damage was also evaluated in blood of these animals. Some parameters were also evaluated in cerebellum from neonatal rats and in cerebellum neuronal cultures. Prist significantly increased malondialdehyde (MDA) levels and carbonyl formation and reduced sulfhydryl content and glutathione (GSH) concentrations in cerebellum of young rats. It also caused DNA strand damage in cerebellum and induced a high micronuclei frequency in blood. On the other hand, this fatty acid significantly reduced α-ketoglutarate dehydrogenase and aconitase activities in rat cerebellum. We also verified that Prist-induced increase of MDA levels was totally prevented by melatonin and attenuated by α-tocopherol but not by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester, indicating the involvement of reactive oxygen species in this effect. Cerebellum from neonate rats also showed marked alterations of redox homeostasis, including an increase of MDA levels and a decrease of sulfhydryl content and GSH concentrations elicited by Prist. Finally, Prist provoked an increase of dichlorofluorescein (DCFH) oxidation in cerebellum-cultivated neurons. Our present data indicate that Prist compromises redox homeostasis in rat cerebellum and blood and inhibits critical enzymes of the citric acid cycle that are susceptible to free radical attack. The present findings may contribute to clarify the pathogenesis of the cerebellar alterations observed in patients affected by ZS and some peroxisomal disorders in which Prist is accumulated.
    Cerebellum (London, England). 08/2014;
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    ABSTRACT: The role of excitotoxicity on the neuropathology of glutaric acidemia type I (GA I) is still under debate. Therefore, in the present work we evaluated glutamate uptake by brain slices and glutamate binding to synaptic membranes, as well as glutamine synthetase activity in cerebral cortex and striatum from glutaryl-CoA dehydrogenase deficient (Gcdh−/−) mice along development (7-, 15-, 30- and 60 days of life) in the hopes to clarify this matter. We also tested the influence of glutaric acid (GA) added exogenously on these parameters. [3H] Glutamate uptake was not significantly altered in cerebral cortex and striatum from Gcdh−/− mice, as compared to WT mice. However, GA provoked a significant decrease of [3H] glutamate uptake in striatum from both WT and Gcdh−/− mice older than 7 days. This inhibitory effect was more pronounced in Gcdh−/−, as compared to WT mice. The use of a competitive inhibitor of glutamate astrocytic transporters indicated that the decrease of [3H] glutamate uptake caused by GA was due to a competition between this organic acid and glutamate for the same astrocytic transporter site. We also found that Na+- dependent [3H] glutamate binding (binding to transporters) was increased in striatum from Gcdh−/− mice and that GA significantly diminished this binding both in striatum and cerebral cortex from Gcdh−/−, but not from WT mice. Finally, we observed that glutamine synthetase activity was not changed in brain cortex and striatum from Gcdh−/− and WT mice and that GA was not able to alter this activity. It is therefore presumed that a disturbance of the glutamatergic neurotransmission system caused by GA may potentially be involved in the neuropathology of GA I, particularly in the striatum.
    Journal of the Neurological Sciences. 01/2014;
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    ABSTRACT: Peroxisomal biogenesis disorders (PBD) are inherited disorders clinically manifested by neurological symptoms and brain abnormalities, in which the cerebellum is usually involved. Biochemically, patients affected by these neurodegenerative diseases accumulate branched-chain fatty acids, including pristanic acid (Prist) in the brain and other tissues. In the present investigation we studied the in vitro influence of Prist, at doses found in PBD, on oxidative phosphorylation, by measuring the activities of the respiratory chain complexes I-IV and ATP production, as well as on creatine kinase and synaptic Na(+), K(+)- ATPase activities in rat cerebellum. Prist significantly decreased complexes I-III (65 %), II (40 %) and especially II-III (90 %) activities, without altering the activities of complex IV of the respiratory chain and creatine kinase. Furthermore, ATP formation and synaptic Na(+), K(+)- ATPase activity were markedly inhibited (80-90 %) by Prist. We also observed that this fatty acid altered mitochondrial and synaptic membrane fluidity that may have contributed to its inhibitory effects on the activities of the respiratory chain complexes and Na(+), K(+)- ATPase. Considering the importance of oxidative phosphorylation for mitochondrial homeostasis and of Na(+), K(+)- ATPase for the maintenance of cell membrane potential, the present data indicate that Prist compromises brain bioenergetics and neurotransmission in cerebellum. We postulate that these pathomechanisms may contribute to the cerebellar alterations observed in patients affected by PBD in which Prist is accumulated.
    Life sciences 11/2013; · 2.56 Impact Factor
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    ABSTRACT: Isolated 3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an autosomal recessive disorder of leucine metabolism biochemically characterized by accumulation of 3-methylcrotonylglycine (3MCG), 3-methylcrotonic acid (3MCA) and 3-hydroxyisovaleric acid. A considerable number of affected individuals present neurological symptoms with or without precedent crises of metabolic decompensation and brain abnormalities whose pathogenesis is poorly known. We investigated the in vitro effects of 3MCG and 3MCA on important parameters of oxidative stress in cerebral cortex of young rats. 3MCG and 3MCA significantly increased TBA-RS and carbonyl formation, indicating that these compounds provoke lipid and protein oxidation, respectively. In contrast, nitric oxide production was not affected by 3MCG and 3MCA. Furthermore, 3MCG- and 3MCA-induced elevation of TBA-RS values was fully prevented by melatonin, trolox and reduced glutathione, but not by the nitric oxide inhibitor N(ω)-nitro-L-arginine methyl ester or the combination of catalase plus superoxide dismutase, indicating that reactive oxygen species were involved in the oxidative damage caused by these compounds. We also found that the activity of the antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase and glutathione reductase were not altered in vitro by 3MCG and 3MCA. It is therefore presumed that alterations of the cellular redox homeostasis caused by the major metabolites accumulating in 3MCCD may potentially be involved in the pathophysiology of the neurological dysfunction and structural brain alterations found in patients affected by this disorder.
    Cellular and Molecular Neurobiology 09/2012; · 2.29 Impact Factor
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    ABSTRACT: Hyperornithinemia is the biochemical hallmark of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2-5 μmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.
    Metabolic Brain Disease 06/2012; · 2.33 Impact Factor