Glutaric acid induces oxidative stress in brain of young rats

Marques, Fernanda de Oliveira; Hagen, Martine Elisabeth Kienzle; Pederzolli, Carolina Didonet; Sgaravatti, Ângela Malysz; Durigon, Karina; Testa, Carla Giordani; Wannmacher, Clóvis Milton Duval; Wyse, Ângela T. S.; Wajner, Moaçir; Dutra-Filho, Carlos Severo

doi:10.1016/s0006-8993(02)04118-5

Cited by 79 publications

(48 citation statements)

References 22 publications

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“…Mechanistically, reduction of GPx activity may result from modification of enzyme active sites (e.g., free-radical attack by reactive species), as has been demonstrated for other neurodegenerative disorders in which oxidative stress occurs (de Oliveira Marques et al 2003;Schweizer et al 2004;Sian et al 1999). Of interest, the pattern of antioxidant alterations found in the present investigation, i.e., reduction of GPx and increase of SOD activities, has been found in brain from patients affected by Parkinson disease, in which oxidative stress plays an important role (Sian et al 1999).…”

Section: Discussionmentioning

confidence: 97%

Evidence for oxidative stress in tissues derived from succinate semialdehyde dehydrogenase‐deficient mice

Latini

Scussiato

Leipnitz

et al. 2007

J of Inher Metab Disea

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Animal models of inborn errors of metabolism are useful for investigating the pathogenesis associated with the corresponding human disease. Since the mechanisms involved in the pathophysiology of succinate semialdehyde dehydrogenase (SSADH) deficiency (Aldh5a1; OMIM 271980) are still not established, in the present study we evaluated the tissue antioxidant defences and lipid peroxidation in various cerebral structures (cortex, cerebellum, thalamus and hippocampus) and in the liver of SSADH-deficient mice. The parameters analysed were total radical-trapping antioxidant potential (TRAP) and glutathione (GSH) levels, the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as thiobarbituric acid-reactive substances (TBARS). We first observed that the tissue nonenzymatic antioxidant defences were significantly reduced in the SSADH-deficient animals, particularly in the liver (decreased TRAP and GSH) and in the cerebral cortex (decreased GSH), as compared to the wild-type mice. Furthermore, SOD activity was significantly increased in the liver and cerebellum, whereas the activity of CAT was significantly higher in the thalamus. In contrast, GPx activity was significantly diminished in the hippocampus. Finally, we observed that lipid peroxidation (TBARS levels) was markedly increased in the liver and cerebral cortex, reflecting a high lipid oxidative damage in these tissues. Our data showing an imbalance between tissue antioxidant defences and oxidative attack strongly indicate that oxidative stress is involved in the pathophysiology of SSADH deficiency in mice, and likely the corresponding human disorder.

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Section: Discussionmentioning

confidence: 97%

Evidence for oxidative stress in tissues derived from succinate semialdehyde dehydrogenase‐deficient mice

Latini

Scussiato

Leipnitz

et al. 2007

J of Inher Metab Disea

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“…Electrons can be transferred by ETFDH to ubiquinone entering the mitochondrial respiratory chain (59). Deficiency in ETFDH leads to accumulation of glutaric acid resulting in increased oxidative stress (52). We have measured a decrease in Etfdh expression in ALR compared with NOD (data not shown).…”

Section: Ros Generatormentioning

confidence: 89%

Nuclear and Mitochondrial Interaction Involving mt-Nd2 Leads to Increased Mitochondrial Reactive Oxygen Species Production

Gusdon

Votyakova

Reynolds

et al. 2007

Journal of Biological Chemistry

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NADH dehydrogenase subunit 2, encoded by the mtDNA, has been associated with resistance to autoimmune type I diabetes (T1D) in a case control study. Recently, we confirmed a role for the mouse ortholog of the protective allele (mt-Nd2 a ) in resistance to T1D using genetic analysis of outcrosses between T1D-resistant ALR and T1D-susceptible NOD mice. We sought to determine the mechanism of disease protection by elucidating whether mt-Nd2 a affects basal mitochondrial function or mitochondrial function in the presence of oxidative stress. Two lines of reciprocal conplastic mouse strains were generated: one with ALR nuclear DNA and NOD mtDNA (ALR.mt NOD ) and the reciprocal with NOD nuclear DNA and ALR mtDNA (NOD.mt ALR ). Basal mitochondrial respiration, transmembrane potential, and electron transport system enzymatic activities showed no difference among the strains. However, ALR.mt NOD mitochondria supported by either complex I or complex II substrates produced significantly more reactive oxygen species when compared with both parental strains, NOD.mt ALR or C57BL/6 controls. Nitric oxide inhibited respiration to a similar extent for mitochondria from the five strains due to competitive antagonism with molecular oxygen at complex IV. Superoxide and hydrogen peroxide generated by xanthine oxidase did not significantly decrease complex I function. The protein nitrating agents peroxynitrite or nitrogen dioxide radicals significantly decreased complex I function but with no significant difference among the five strains. In summary, mt-Nd2 a does not confer elevated resistance to oxidative stress; however, it plays a critical role in the control of the mitochondrial reactive oxygen species production.Single nucleotide polymorphisms in the mtDNA have been associated with degenerative diseases and various cancers. Yet sequence changes may also result in resistance to disease.Indeed, a cytosine to adenine transversion (C5178A) resulting in a leucine to methionine substitution in the human NADH dehydrogenase subunit 2 gene (mt-ND2) encoded in the mtDNA has been associated with increased longevity (1, 2) as well as reductions in atherosclerosis (3), blood pressure (4), myocardial infarction (5), and T1D 3 incidence (6). The adenine-containing allele, mt-ND2 a (adenine containing NADH dehydrogenase subunit 2 allele), was also associated with reduced islet autoimmunity as represented by significantly lower titers of autoantibodies against glutamic acid decarboxylase, insulin, and protein-tyrosine phosphatase, receptor type N (Ptprn or IA-2) (6).Insulin synthetic and secretory capacities of pancreatic ␤ cells are highly dependent upon communication between the nucleus and the mitochondria (7) and are reliant upon mitochondrial ATP generation (8). Although mitochondria are critical for the life and function of ␤ cells, there is strong evidence that mitochondria play a central role in apoptotic death of the ␤ cell during autoimmune T1D (9 -16). Therefore, sequence variation in the mtDNA may have profound effects on the ␤ cell...

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“…In fact, oxidative stress has been implicated in the pathophysiology of common neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, epileptic seizures and demyelination (Halliwell and Gutteridge 1996; Pérez-Severiano et al 2000;Bogdanov et al 2001;Karelson et al 2001;Méndez-Alvarez et al 2001;Behl and Moosmann 2002a, b;Stoy et al 2005;Berg and Youdim 2006;Mancuso et al 2007). Furthermore, there is compelling evidence that oxidative stress occurs in a variety of inborn errors of metabolism, including organic acidemias (Moyano et al 1997;Colome et al 2000;Fontella et al 2000;Kölker et al 2001a, b;de Oliveira Marques et al 2003;Fighera et al 2003;Latini et al 2003a, b;Wajner et al 2004) and other inherited metabolic disorders, such as tyrosinemia type I, Rett syndrome, X-linked adrenoleukodystrophy, Lesh-Nyhan disease, urea cycle defects and homocystinuria (Bird et al 1995;Sierra et al 2001;Streck et al 2001Streck et al , 2003Vargas et al 2004). …”

Section: Discussionmentioning

confidence: 99%

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

et al. 2009

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High levels of phenylalanine (Phe) are the biochemical hallmark of phenylketonuria (PKU), a neurometabolic disorder clinically characterized by severe mental retardation and other brain abnormalities, including cortical atrophy and microcephaly. Considering that the pathomechanisms leading to brain damage and particularly the marked cognitive impairment in this disease are poorly understood, in the present study we investigated the in vitro effect of Phe, at similar concentrations as to those found in brain of PKU patients, on important parameters of oxidative stress in the hippocampus and cerebral cortex of developing rats. We found that Phe induced in vitro lipid peroxidation (increase of TBA-RS values) and protein oxidative damage (sulfhydryl oxidation) in both cerebral structures. Furthermore, these effects were probably mediated by reactive oxygen species, since the lipid oxidative damage was totally prevented by the free radical scavengers alpha-tocopherol and melatonin, but not by L-NAME, a potent inhibitor of nitric oxide synthase. Accordingly, Phe did not induce nitric oxide synthesis, but significantly decreased the levels of reduced glutathione (GSH), the major brain antioxidant defense, in hippocampus and cerebral cortex supernatants. Phe also reduced the thiol groups of a commercial GSH solution in a cell-free medium. We also found that the major metabolites of Phe catabolism, phenylpyruvate, phenyllactate and phenylacetate also increased TBA-RS levels in cerebral cortex, but to a lesser degree. The data indicate that Phe elicits oxidative stress in the hippocampus, a structure mainly involved with learning/memory, and also in the cerebral cortex, which is severely damaged in PKU patients. It is therefore presumed that this pathomechanism may be involved at least in part in the severe cognitive deficit and in the characteristic cortical atrophy associated with dysmyelination and leukodystrophy observed in this disorder.

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Glutaric acid induces oxidative stress in brain of young rats

Cited by 79 publications

References 22 publications

Evidence for oxidative stress in tissues derived from succinate semialdehyde dehydrogenase‐deficient mice

Evidence for oxidative stress in tissues derived from succinate semialdehyde dehydrogenase‐deficient mice

Nuclear and Mitochondrial Interaction Involving mt-Nd2 Leads to Increased Mitochondrial Reactive Oxygen Species Production

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

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