Glutaric Acid Administration Impairs Energy Metabolism in Midbrain and Skeletal Muscle of Young Rats

Ferreira, Gustavo da Costa; Viegas, Carolina Maso; Schuck, Patrícia Fernanda; Tonin, Anelise Miotti; Ribeiro, César Augusto João; Coelho, Daniella de Moura; Costa, Teresa Dalla; Latini, Alexandra; Wyse, Ângela T. S.; Wannmacher, Clóvis Milton Duval; Vargas, Carmen Regla; Wajner, Moaçir

doi:10.1007/s11064-005-7711-9

Cited by 31 publications

(39 citation statements)

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“…We have recently reported that acute administration of GA to developing rats induce brain GA concentrations similar to those found in brain of GAI patients and cause a specific inhibition of the respiratory chain in midbrain, but not in other brain structures (Ferreira et al, 2005). In the present investigation, we report the effects of chronic (5-22 days of postnatal life) and acute subcutaneous administration of GA to developing rats on various parameters of oxidative stress in brain, skeletal muscle, heart, liver, and blood.…”

Section: Introductionmentioning

confidence: 73%

“…Rats from 5 to 22 days of postnatal life were subcutaneously administered with three daily injections of GA (5 µmol/g body weight) buffered with NaOH to pH 7.4 and killed by decapitation 12 h after the last injection (Ferreira et al, 2005). GA treatment resulted in maximal tissue GA concentrations of 6 mM in plasma, 4 µmol/g fresh tissue (∼ 4 mM) in skeletal muscle, heart, and liver 15-30 min after injection and 0.6 µmol/g fresh tissue (∼ 0.6 mM) in the brain 60-90 min after injection (Ferreira et al, 2005).…”

Section: Chronic Ga Treatmentmentioning

confidence: 99%

“…GA treatment resulted in maximal tissue GA concentrations of 6 mM in plasma, 4 µmol/g fresh tissue (∼ 4 mM) in skeletal muscle, heart, and liver 15-30 min after injection and 0.6 µmol/g fresh tissue (∼ 0.6 mM) in the brain 60-90 min after injection (Ferreira et al, 2005).…”

Section: Chronic Ga Treatmentmentioning

confidence: 99%

“…The primary cause of striatum degeneration in GAI is still not defined despite the intense investigations performed using different in vitro systems where brain tissue was exposed to the metabolites accumulating in GAI (Kölker et al, 1999(Kölker et al, , 2000(Kölker et al, , 2001a(Kölker et al, ,b, 2002aKoeller et al, 2002;Latini et al, 2002Latini et al, , 2005ade Oliveira Marques et al, 2003;Ferreira et al, 2005). Data merging from these studies suggest that GA and 3-HGA can induce brain damage by primary or secondary excitotoxicity (Kölker et al, 1999(Kölker et al, , 2000(Kölker et al, , 2002ade Mello et al, 2001;Frizzo et al, 2004;Porciuncula et al, 2004;Rosa et al, 2004), oxidative stress (Latini et al, 2002(Latini et al, , 2005bde Oliveira Marques et al, 2003), or energy depletion (Ullrich et al, 1999;Silva et al, 2000;Das et al, 2003;Ferreira et al, 2005;Latini et al, 2005a).…”

Section: Introductionmentioning

confidence: 99%

“…Data merging from these studies suggest that GA and 3-HGA can induce brain damage by primary or secondary excitotoxicity (Kölker et al, 1999(Kölker et al, , 2000(Kölker et al, , 2002ade Mello et al, 2001;Frizzo et al, 2004;Porciuncula et al, 2004;Rosa et al, 2004), oxidative stress (Latini et al, 2002(Latini et al, , 2005bde Oliveira Marques et al, 2003), or energy depletion (Ullrich et al, 1999;Silva et al, 2000;Das et al, 2003;Ferreira et al, 2005;Latini et al, 2005a). Furthermore, it has been suggested that these mechanisms might cooperate in a synergistic way to cause the neuropathological alterations found in GAI patients (Kölker et al, 2004;Wajner et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Induction of Oxidative Stress by Chronic and Acute Glutaric Acid Administration to Rats

et al. 2007

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: 1. Glutaric acidemia type I (GA I) is a neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase, which leads to tissue accumulation of predominantly glutaric acid (GA) and also 3-hydroxyglutaric acid to a lesser amount. Affected patients usually present progressive cortical atrophy and acute striatal degeneration attributed to the toxic accumulating metabolites.2. In the present study, we determined a number of oxidative stress parameters, namely chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total antioxidant reactivity (TAR), glutathione (GSH) levels, and the activities of catalase and glutathione peroxidase (GPx), in various tissues from rats chronically exposed to GA or to saline (controls). High GA concentrations, similar to those found in glutaric aciduria type I, were induced in the brain by three daily subcutaneous injections of saline-buffered GA (5 micromol/g body weight) to Wistar rats of 5-22 days of life. The parameters were assessed 12 h after the last GA administration in different brain structures, skeletal muscle, heart, liver, erythrocytes, and plasma. The lipid peroxidation parameters chemiluminescence and/or TBA-RS measurements were found significantly increased in midbrain, liver, and erythrocytes of GA-injected rats. The activity of GPx was significantly reduced in midbrain and markedly increased in liver. TAR measurement was significantly reduced in midbrain and liver. Furthermore, GSH levels were reduced in liver and heart. We also investigated the acute in vivo effect of GA administration on the same oxidative stress parameters in cerebral structures and erythrocytes from 22-day-old rats. We found that TBA-RS values were significantly increased in erythrocytes, TAR levels were markedly decreased in midbrain and cerebellum, and GPx activity mildly reduced in the midbrain.3. These data showing an imbalance between antioxidant defences and oxidative damage, particularly in midbrain, liver, and erythrocytes from GA-injected rats, indicate that oxidative stress might be involved in GA toxicity and that the midbrain, where the striatum is located, is the brain structure more susceptible to GA chronic and acute exposition.

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Section: Introductionmentioning

confidence: 73%

Section: Chronic Ga Treatmentmentioning

confidence: 99%

Section: Chronic Ga Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induction of Oxidative Stress by Chronic and Acute Glutaric Acid Administration to Rats

et al. 2007

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Biochemistry and bioenergetics of glutaryl‐CoA dehydrogenase deficiency

Sauer

2007

J of Inher Metab Disea

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Glutaryl-CoA dehydrogenase (GCDH) is a central enzyme in the catabolic pathway of L-tryptophan, L-lysine, and L-hydroxylysine which catalyses the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO2. Glutaryl-CoA dehydrogenase deficiency (GDD) is an autosomal recessive disease characterized by the accumulation of glutaric and 3-hydroxyglutaric acids in tissues and body fluids. Untreated patients commonly present with severe striatal degeneration during encephalopathic crises. Previous studies have highlighted primary excitotoxicity as a trigger of striatal degeneration. The aim of this PhD study was to investigate in detail tissue-specific bioenergetic and biochemical parameters of GDD in vitro, post mortem, and in Gcdh-/- mice. The major bioenergetic finding was uncompetitive inhibition of alpha-ketoglutarate dehydrogenase complex by glutaryl-CoA. It is suggested that a synergism of primary and secondary excitotoxic effects in concert with age-related physiological changes in the developing brain underlie acute and chronic neurodegenerative changes in GDD patients. The major biochemical findings were highly elevated cerebral concentrations of glutaric and 3-hydroxyglutaric acid despite low permeability of the blood-brain barrier for these dicarboxylic acids. It can be postulated that glutaric and 3-hydroxyglutaric acids are synthesized de novo and subsequently trapped in the brain. In this light, neurological disease in GDD is not 'transported' to the brain in analogy with phenylketonuria or hepatic encephalopathy as suggested previously but is more likely to be induced by the intrinsic biochemical properties of the cerebral tissue and the blood-brain barrier.

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Age and Brain Structural Related Effects of Glutaric and 3-Hydroxyglutaric Acids on Glutamate Binding to Plasma Membranes During Rat Brain Development

et al. 2007

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(1) In the present study we determined the effects of glutaric (GA, 0.01-1 mM) and 3-hydroxyglutaric (3-OHGA, 1.0-100 microM) acids, the major metabolites accumulating in glutaric acidemia type I (GA I), on Na(+)-independent and Na(+)-dependent [(3)H]glutamate binding to synaptic plasma membranes from cerebral cortex and striatum of rats aged 7, 15 and 60 days. (2) GA selectively inhibited Na(+)-independent [(3)H]glutamate binding (binding to receptors) in cerebral cortex and striatum of rats aged 7 and 15 days, but not aged 60 days. In contrast, GA did not alter Na(+)-dependent glutamate binding (binding to transporters) to synaptic membranes from brain structures of rats at all studied ages. Furthermore, experiments using the glutamatergic antagonist CNQX indicated that GA probably binds to non-NMDA receptors. In addition, GA markedly inhibited [(3)H]kainate binding to synaptic plasma membranes in cerebral cortex of 15-day-old rats, indicating that this effect was probably directed towards kainate receptors. On the other hand, experiments performed with 3-OHGA revealed that this organic acid did not change Na(+)-independent [(3)H]glutamate binding to synaptic membranes from cerebral cortex and striatum of rats from all ages, but inhibited Na(+)-dependent [(3)H]glutamate binding to membranes in striatum of 7-day-old rats, but not in striatum of 15- and 60-day-old rats and in cerebral cortex of rats from all studied ages. We also provided some evidence that 3-OHGA competes with the glutamate transporter inhibitor L-trans-pyrrolidine-2,4-dicarboxylate, suggesting a possible interaction of 3-OHGA with glutamate transporters on synaptic membranes. (3) These results indicate that glutamate binding to receptors and transporters can be inhibited by GA and 3-OHGA in cerebral cortex and striatum in a developmentally regulated manner. It is postulated that a disturbance of glutamatergic neurotransmission caused by the major metabolites accumulating in GA I at early development may possibly explain, at least in part, the window of vulnerability of striatum and cerebral cortex to injury in patients affected by this disorder.

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Glutaric Acid Administration Impairs Energy Metabolism in Midbrain and Skeletal Muscle of Young Rats

Cited by 31 publications

References 40 publications

Induction of Oxidative Stress by Chronic and Acute Glutaric Acid Administration to Rats

Induction of Oxidative Stress by Chronic and Acute Glutaric Acid Administration to Rats

Biochemistry and bioenergetics of glutaryl‐CoA dehydrogenase deficiency

Age and Brain Structural Related Effects of Glutaric and 3-Hydroxyglutaric Acids on Glutamate Binding to Plasma Membranes During Rat Brain Development

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