Promotion of Oxidative Stress by 3-hydroxyglutaric Acid in Rat Striatum

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2005 Feb 11

PMID 15702406

Citations 14

Authors

A Latini

K Scussiato

G Leipnitz

C S Dutra-Filho

M Wajner

Affiliations

Soon will be listed here.

Abstract

The pathophysiology of the striatum degeneration characteristic of patients affected by the inherited neurometabolic disorder glutaryl-CoA dehydrogenase deficiency (GDD), also known as glutaric aciduria type I, is still in debate. We have previously reported that 3-hydroxyglutaric acid (3-OH-GA) considered the main neurotoxin in this disorder, induces oxidative stress in rat cerebral cotex. In the present work, we extended these studies by investigating the in vitro effect of 3-OH-GA, at concentrations ranging from 0.01 to 1.0 mmol/L on the brain antioxidant defences by measuring total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and glutathione (GSH) levels, and on the production of hydrogen peroxide (H(2)O(2)), nitric oxide (NO) and malondialdehyde in striatum homogenates from young rats. We observed that TRAP, TAR and GSH levels were markedly reduced (by up to 50%) when striatum homogenates were treated with 3-OH-GA. In contrast, H(2)O(2) (up to 44%), NO (up to 95%) and malondialdehyde levels (up to 28%) were significantly increased by 3-OH-GA. These data indicate that total nonenzymatic antioxidant defences (TRAP) and the tissue capacity to handle an increase of reactive species (TAR) were reduced by 3-OH-GA in the striatum. Furthermore, the results also reflect an increase of lipid peroxidation, probably secondary to 3-OH-GA-induced free radical production. Thus, it may be presumed that oxidative stress is involved in the neuropathology in GDD.

Citing Articles

Disturbance of Mitochondrial Dynamics, Endoplasmic Reticulum-Mitochondria Crosstalk, Redox Homeostasis, and Inflammatory Response in the Brain of Glutaryl-CoA Dehydrogenase-Deficient Mice: Neuroprotective Effects of Bezafibrate.

Seminotti B, Brondani M, Ribeiro R, Leipnitz G, Wajner M Mol Neurobiol. 2022; 59(8):4839-4853.

PMID: 35639256 DOI: 10.1007/s12035-022-02887-3.

Toxic Synergism Between Quinolinic Acid and Glutaric Acid in Neuronal Cells Is Mediated by Oxidative Stress: Insights to a New Toxic Model.

Pierozan P, Colin-Gonzalez A, Biasibetti H, da Silva J, Wyse A, Wajner M Mol Neurobiol. 2017; 55(6):5362-5376.

PMID: 28936789 DOI: 10.1007/s12035-017-0761-6.

Oxidative Stress, Disrupted Energy Metabolism, and Altered Signaling Pathways in Glutaryl-CoA Dehydrogenase Knockout Mice: Potential Implications of Quinolinic Acid Toxicity in the Neuropathology of Glutaric Acidemia Type I.

Seminotti B, Amaral A, Ribeiro R, Rodrigues M, Colin-Gonzalez A, Leipnitz G Mol Neurobiol. 2015; 53(9):6459-6475.

PMID: 26607633 DOI: 10.1007/s12035-015-9548-9.

Increased glutamate receptor and transporter expression in the cerebral cortex and striatum of gcdh-/- mice: possible implications for the neuropathology of glutaric acidemia type I.

Lagranha V, Matte U, Carvalho T, Seminotti B, Pereira C, Koeller D PLoS One. 2014; 9(3):e90477.

PMID: 24594605 PMC: 3942441. DOI: 10.1371/journal.pone.0090477.

Effects of targeted suppression of glutaryl-CoA dehydrogenase by lentivirus-mediated shRNA and excessive intake of lysine on apoptosis in rat striatal neurons.

Gao J, Zhang C, Fu X, Yi Q, Tian F, Ning Q PLoS One. 2013; 8(5):e63084.

PMID: 23658800 PMC: 3642093. DOI: 10.1371/journal.pone.0063084.

References

Forstner R, Hoffmann G, Gassner I, Heideman P, De Klerk J, Doringer E . Glutaric aciduria type I: ultrasonographic demonstration of early signs. Pediatr Radiol. 1999; 29(2):138-43. DOI: 10.1007/s002470050558. View

Soffer D, Amir N, Elpeleg O, Gomori J, Shalev R . Striatal degeneration and spongy myelinopathy in glutaric acidemia. J Neurol Sci. 1992; 107(2):199-204. DOI: 10.1016/0022-510x(92)90289-w. View

Latini A, Borba Rosa R, Scussiato K, Llesuy S, Bello-Klein A, Wajner M . 3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defenses in cerebral cortex of young rats. Brain Res. 2002; 956(2):367-73. DOI: 10.1016/s0006-8993(02)03573-4. View

Hevel J, Marletta M . Nitric-oxide synthase assays. Methods Enzymol. 1994; 233:250-8. DOI: 10.1016/s0076-6879(94)33028-x. View

Gonzalez Flecha B, Llesuy S, Boveris A . Hydroperoxide-initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver, and muscle. Free Radic Biol Med. 1991; 10(2):93-100. DOI: 10.1016/0891-5849(91)90002-k. View

Kolker S, Okun J, Ahlemeyer B, Wyse A, Horster F, Wajner M . Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons. J Neurosci Res. 2002; 68(4):424-31. DOI: 10.1002/jnr.10189. View

Rothe G, Valet G . Flow cytometric analysis of respiratory burst activity in phagocytes with hydroethidine and 2',7'-dichlorofluorescin. J Leukoc Biol. 1990; 47(5):440-8. View

Das A . Regulation of the mitochondrial ATP-synthase in health and disease. Mol Genet Metab. 2003; 79(2):71-82. DOI: 10.1016/s1096-7192(03)00069-6. View

Kolker S, Ahlemeyer B, Krieglstein J, Hoffmann G . 3-Hydroxyglutaric and glutaric acids are neurotoxic through NMDA receptors in vitro. J Inherit Metab Dis. 1999; 22(3):259-62. DOI: 10.1023/a:1005577920954. View

10.

Lissi E, Pascual C, Del Castillo M . Evaluation of total antioxidant potential (TRAP) and total antioxidant reactivity from luminol-enhanced chemiluminescence measurements. Free Radic Biol Med. 1995; 18(2):153-8. DOI: 10.1016/0891-5849(94)00117-3. View

11.

Das A, Lucke T, Ullrich K . Glutaric aciduria I: creatine supplementation restores creatinephosphate levels in mixed cortex cells from rat incubated with 3-hydroxyglutarate. Mol Genet Metab. 2003; 78(2):108-11. DOI: 10.1016/s1096-7192(02)00227-5. View

12.

Sawada G, Raub T, Decker D, Buxser S . Analytical and numerical techniques for the evaluation of free radical damage in cultured cells using scanning laser microscopy. Cytometry. 1996; 25(3):254-62. DOI: 10.1002/(SICI)1097-0320(19961101)25:3<254::AID-CYTO6>3.0.CO;2-F. View

13.

Strauss K, Puffenberger E, Robinson D, Morton D . Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet. 2003; 121C(1):38-52. DOI: 10.1002/ajmg.c.20007. View

14.

Kolker S, Ahlemeyer B, Huhne R, Mayatepek E, Krieglstein J, Hoffmann G . Potentiation of 3-hydroxyglutarate neurotoxicity following induction of astrocytic iNOS in neonatal rat hippocampal cultures. Eur J Neurosci. 2001; 13(11):2115-22. DOI: 10.1046/j.0953-816x.2001.01595.x. View

15.

de Mello C, Kolker S, Ahlemeyer B, de Souza F, Fighera M, Mayatepek E . Intrastriatal administration of 3-hydroxyglutaric acid induces convulsions and striatal lesions in rats. Brain Res. 2001; 916(1-2):70-5. DOI: 10.1016/s0006-8993(01)02865-7. View

16.

Hoffmann G, Zschocke J . Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis. 1999; 22(4):381-91. DOI: 10.1023/a:1005543904484. View

17.

LeBel C, Ischiropoulos H, Bondy S . Evaluation of the probe 2',7'-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol. 1992; 5(2):227-31. DOI: 10.1021/tx00026a012. View

18.

Wilhelm J, Vankova M, Maxova H, Siskova A . Hydrogen peroxide production by alveolar macrophages is increased and its concentration is elevated in the breath of rats exposed to hypoxia: relationship to lung lipid peroxidation. Physiol Res. 2003; 52(3):327-32. View

19.

Goodman S, Norenberg M, Shikes R, Breslich D, Moe P . Glutaric aciduria: biochemical and morphologic considerations. J Pediatr. 1977; 90(5):746-50. DOI: 10.1016/s0022-3476(77)81240-7. View

20.

Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi E . Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols. Arch Biochem Biophys. 2001; 388(2):261-6. DOI: 10.1006/abbi.2001.2292. View