Inhibition of energy productionin vitro by glutaric acid in cerebral cortex of young rats

Silva, C. G.; Silva, A. R.; Ruschel, Carla Felippi Chiella; Helegda, C.; Wyse, Angela T. S.; Wannmacher, C. M. D.; Dutra-Filho, Carlos Severo; Wajner, Moaçir

doi:10.1007/bf02679979

Cited by 29 publications

(26 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Little is known about cerebrospinal fluid and brain tissue concentrations of GA and its metabolites in GDD patients (1), and there is a complete lack of fetal data. Whereas in most experimental settings described in this article, oligodendrocyte apoptosis was observed with concentrations as little as 0.1 mM, neuronal apoptosis was elicited experimentally using higher concentrations, up to 50 mM (2)(3)(4)17,21,30). Moreover, although experiments have been performed with GA, 3-OH-GA, or GC, all three substances are present within in vivo situations.…”

Section: Discussionmentioning

confidence: 91%

Glutaric Acid and Its Metabolites Cause Apoptosis in Immature Oligodendrocytes: A Novel Mechanism of White Matter Degeneration in Glutaryl-CoA Dehydrogenase Deficiency

et al. 2005

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 91%

Glutaric Acid and Its Metabolites Cause Apoptosis in Immature Oligodendrocytes: A Novel Mechanism of White Matter Degeneration in Glutaryl-CoA Dehydrogenase Deficiency

et al. 2005

View full text Add to dashboard Cite

“…Previously, we have demonstrated in rat cortex homogenates that GA significantly inhibited in vitro the rate of ATP synthesis, as well as complex I--III activity at 2.5 and 5.0 mM concentrations and complex II--III activity at 5.0 mM GA (37). Therefore, it may be concluded that GA-induced inhibition of energy metabolism in the brain is not specifically directed toward the striatum and probably cannot solely explain the striatal degeneration occurring in GAI patients as recently hypothesized (2).…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2005

View full text Add to dashboard Cite

A genetic mice model of glutaric acidemia type I (GAI) has recently been developed, however affected animals do not develop the striatal damage characteristic of patients with this disorder. Therefore, the initial aim of the present work was to induce high glutaric acid (GA) concentrations in rat brain similar to those found in GAI patients through subcutaneous injection of GA. High brain GA concentrations (up to 0.60 micromol/g congruent with 0.60mM) were achieved by a single subcutaneous injection of saline-buffered GA (5 micromol/g body weight) to Wistar rats of 7-22 days of life. GA brain levels were about 10-fold lower than in plasma and 5-fold lower than in skeletal and cardiac muscles, indicating that the permeability of the blood brain barrier to GA is low. We also aimed to use this model to investigate neurochemical parameters in the animals. Thus, we evaluated the effect of this model on energy metabolism parameters in midbrain, in which the striatum is localized, as well as in peripheral tissues (skeletal and cardiac muscles) of 22-day-old rats. Control rats were treated with saline in the same volumes. We verified that CO2 production from glucose was not altered in midbrain of rats treated with GA, indicating a normal functioning of the tricarboxylic acid cycle. Creatine kinase activity was also not changed in midbrain, skeletal and cardiac muscles. In contrast, complex I-III activity of the respiratory chain was inhibited in midbrain (25%), while complexes I-III (25%) and II-III (15%) activities were reduced in skeletal muscle, with no alterations found in cardiac muscle. These data indicate that GA administration moderately impairs cellular energy metabolism in midbrain and skeletal muscle of young rats.

show abstract

“…However, in the last decade alterations of energy metabolism (Ullrich et al 1999;Silva et al 2000;Kö lker et al 2002bKö lker et al , 2004Das et al 2003;Latini et al 2005a;da Costa Ferreira et al 2005a, b;Sauer et al 2005), oxidative stress (de Oliveira Marques et al 2003;Latini et al 2002Latini et al , 2005b and particularly disturbance of the glutamatergic system due to the structural similarity between glutamate, GA and 3-OHGA (Flott-Rahmel et al 1997;Lima et al 1998;Kö lker et al 1999Kö lker et al , 2000aKö lker et al , b, 2002aUllrich et al 1999;Porciú ncula et al 2000Porciú ncula et al , 2004Mello et al 2001;Rosa et al 2004;Frizzo et al 2004) have been considered important pathomechanisms underlying neural damage in GA I. On the other hand, recent works performed on neurons in culture did not confirm excitotoxic actions for 3-OHGA (Lund et al 2004;Freudenberg et al 2004), suggesting that more work is necessary to clarify this matter.…”

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

(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.

show abstract

Inhibition of energy productionin vitro by glutaric acid in cerebral cortex of young rats

Cited by 29 publications

References 22 publications

Glutaric Acid and Its Metabolites Cause Apoptosis in Immature Oligodendrocytes: A Novel Mechanism of White Matter Degeneration in Glutaryl-CoA Dehydrogenase Deficiency

Glutaric Acid and Its Metabolites Cause Apoptosis in Immature Oligodendrocytes: A Novel Mechanism of White Matter Degeneration in Glutaryl-CoA Dehydrogenase Deficiency

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

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

Contact Info

Product

Resources

About