Skip to main content
SpringerLink
Log in

The role of oxidative damage in the neuropathology of organic acidurias: Insights from animal studies

  • Published:
Journal of Inherited Metabolic Disease

Abstract

Summary: Organic acidurias represent a group of inherited disorders resulting from deficient activity of specific enzymes of the catabolism of amino acids, carbohydrates or lipids, leading to tissue accumulation of one or more carboxylic (organic) acids. Patients affected by organic acidurias predominantly present neurological symptoms and structural brain abnormalities, of which the aetiopathogenesis is poorly understood. However, in recent years increasing evidence has emerged suggesting that oxidative stress is possibly involved in the pathology of some organic acidurias and other inborn errors of metabolism. This review addresses some of the recent developments obtained mainly from animal studies indicating oxidative damage as an important determinant of the neuropathophysiology of some organic acidurias. Recent data showing that various organic acids are capable of inducing free radical generation and decreasing brain antioxidant defences is presented. The discussion focuses on the relatively low antioxidant defences of the brain and the vulnerability of this tissue to reactive species. This offers new perspectives for potential therapeutic strategies for these disorders, which may include the early use of appropriate antioxidants as a novel adjuvant therapy, besides the usual treatment based on removing toxic compounds and using special diets and pharmacological agents, such as cofactors and L-carnitine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Ali MA, Konishi T (1998) Enhancement of hydroxyl radical generation in the Fenton reaction by alpha-hydroxy acid. Biochem Mol Biol Int 46: 137–145.

    PubMed  CAS  Google Scholar 

  • Barth PG, Hoffmann GF, Jaeken J, et al (1992) L-2-Hydroxyglutaricac iduria: a novel inherited neurometabolicdisease. Ann Neurol 32: 66–71.

    PubMed  CAS  Google Scholar 

  • Barth PG, Hoffmann GF, Jaeken J (1993) L-2-Hydroxyglutaric acid: clinical and biochemical findings in 12 patients and preliminary report on L-2-hydroxyacid dehydrogenase. J Inherit Metab Dis 16: 753–761.

    PubMed  CAS  Google Scholar 

  • Bast A (1993) Oxidative stress and calcium homeostasis. In: Halliwell B, Aruoma OI, eds. DNA and Free Radicals. Chichester: Ellis Horwood, 95–108.

    Google Scholar 

  • Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38: 357–366.

    PubMed  CAS  Google Scholar 

  • Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271: 1424–1437.

    Google Scholar 

  • Bindoli A, Rigobello MP, Deeble DJ (1992) Biochemical and toxicological properties of the oxidation products of catecholamines. Free Radic Biol Med 13: 391–405.

    PubMed  CAS  Google Scholar 

  • Bird S, Miller NJ, Collins JE, Rice-Evans CA (1995) Plasma antioxidant capacity in two cases of tyrosinaemia type 1: one case treated with NTBC. J Inherit Metab Dis 18: 123–126.

    PubMed  CAS  Google Scholar 

  • Boje KM, Arora aemia PK (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587: 250–256.

    PubMed  CAS  Google Scholar 

  • Brannan TS, Maker HS, Raes IP (1981) Regional distribution of CAT in the adult rat brain. J Neurochem 36: 307–309.

    PubMed  CAS  Google Scholar 

  • Bridi R, Araldi J, Sgarbi MB, et al (2003) Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. Int J Dev Neurosci 21: 327–332.

    PubMed  CAS  Google Scholar 

  • Brigelius-Flohe R (1999) Tissue-specific functions of individuals glutathione peroxidases. Free Radic Biol Med 27: 951–965.

    PubMed  CAS  Google Scholar 

  • Brismar J, Ozand PT (1994) CT and MR of the brain in the diagnosis of organicac idurias. Experiences from 107 patients. Brain Dev 16: 104–124

    PubMed  Google Scholar 

  • Brodie AE, Reed DJ (1987) Reversible oxidation of glyceraldehyde 3-phosphate dehydrogenase thiols in human lung carcinoma cells by hydrogen peroxide. Biochem Biophys Res Commun 148: 120–125.

    PubMed  CAS  Google Scholar 

  • Brusque AM, Rotta LN, Tavares RG, et al (2001) Effects of methylmalonic and propionic acids on glutamate uptake by synaptosomes and synapticvesic les and on glutamate release by synaptosomes from cerebral cortex of rats. Brain Res 920: 194–201.

    PubMed  CAS  Google Scholar 

  • Brusque AM, Borba Rosa R, Schuck PF, et al (2002) Inhibition of the mitochondrial respiratory chain complex activities in rat cerebral cortex by methylmalonic acid. Neurochem Int 40: 593–601.

    PubMed  CAS  Google Scholar 

  • Castilho RF, Kowaltowski AJ, Vercesi AE (1996) The irreversibility of inner mitochondrial membrane permeabilization by Ca2+ plus pro-oxidants is determined by the extent of membrane protein thiol cross-linking. J Bioenerg Biomembr 28: 523–529.

    PubMed  CAS  Google Scholar 

  • Castro L, Rodriguez M, Radi R (1994) Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide. J Biol Chem 269: 29409–29415.

    PubMed  CAS  Google Scholar 

  • Castro LA, Robalinho RL, Cayota A, Meneghini R, Radi R (1998) Nitricoxide and peroxynitrite-dependent aconitase inactivation and iron-regulatory protein-1 activation in mammalian fibroblasts. Arch Biochem Biophys 359: 215–224.

    PubMed  CAS  Google Scholar 

  • Chae HZ, Kang SW, Rhee SG (1999) Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. Methods Enzymol 300: 219–226.

    PubMed  CAS  Google Scholar 

  • Chalmers RA, Lawson AM (1982) Organic Acids in Man. Analytical Chemistry, Biochemistry and Diagnosis of the Organic Acidurias. London: Chapman and Hall.

    Google Scholar 

  • Chalmers RA, Purkiss P, Watts RW, Lawson AM (1980) Screening for organic acidurias and amino acidopathies in newborns and children. J Inherit Metab Dis 3: 27–43.

    PubMed  CAS  Google Scholar 

  • Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59: 527–605.

    PubMed  CAS  Google Scholar 

  • Coitinho AS, de Mello CF, Lima TT, de Bastiani J, Figuera MR, Wajner M (2001) Pharmacological evidence that alpha-ketoisovaleric acid induces convulsions through GABAergic and glutamatergicmec hanisms in rats. Brain Res 9: 68–73.

    Google Scholar 

  • Colton C, Wilt S, Gilbert D, Chernyshev O, Snell J, Dubois-Dalcq M(1996) Species differences in the generation of reactive oxygen species by microglia. Mol Chem Neuropathol 28: 15–20.

    PubMed  CAS  Google Scholar 

  • da Silva CG, Bueno AR, Rosa RB, et al (2003a) Inhibition of mitochondrial creatine kinase activity by D-2-hydroxyglutaric acid in cerebellum of young rats. Neurochem Res 28: 1329–1337.

    PubMed  CAS  Google Scholar 

  • da Silva CG, Bueno AR, Schuck PF, et al (2003b) L-2-Hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats. Int J Dev Neurosci 21: 217–224.

    PubMed  CAS  Google Scholar 

  • da Silva CG, Bueno AR, Schuck PF, et al (2003c) D-2-Hydroxyglutaric acid inhibits creatine kinase activity from cardiac and skeletal muscle of young rats. Eur J Clin Invest 33: 840–847.

    PubMed  CAS  Google Scholar 

  • da Silva CG, Bueno AR, Schuck PF, et al (2004) Inhibition of creatine kinase activity from rat cerebral cortex by D-2-hydroxyglutaric acid in vitro. Neurochem Int 44: 45–52.

    PubMed  CAS  Google Scholar 

  • Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65: 1–105.

    PubMed  CAS  Google Scholar 

  • Danielson UH, Esterbauer H, Mannervik B (1987) Structure-activity relationships of 4-hydroxyalkenals in the conjugation catalysed by mammalian glutathione transferases. Biochem J 247: 707–713.

    PubMed  CAS  Google Scholar 

  • de Assis DR, Ribeiro CA, Rosa RB, et al (2003) Evidence that antioxidants prevent the inhibition of Na+,K+-ATPase activity induced by octanoic acid in rat cerebral cortex in vitro. Neurochem Res 28: 1255–1263.

    PubMed  CAS  Google Scholar 

  • de Mello CF, Begnini J, Jimenez-Bernal RE, et al (1996) Intrastriatal methylmalonicac id administration induces rotational behaviour and convulsions through glutamatergic mechanisms. Brain Res 721: 120–125.

    PubMed  CAS  Google Scholar 

  • de Mello CF, Kölker S, Ahlemeyer B, et al (2001) Intrastriatal administration of 3-hydroxyglutaric acid induces convulsions and striatal lesions in rats. Brain Res 916: 70–75.

    PubMed  CAS  Google Scholar 

  • de Oliveira Marques F, Hagen ME, Pederzolli CD (2003) Glutaric acid induces oxidative stress in brain of young rats. Brain Res 964: 153–158.

    PubMed  Google Scholar 

  • Draper HH, Hadley M (1990) A review of recent studies on the metabolism of exogenous and endogenous malondialdehyde. Xenobiotica 20: 901–907.

    PubMed  CAS  Google Scholar 

  • Duez P, Helson M, Some TI, Dubois J, Hanocq M (2000) Chromatographic determination of 8-oxo-7,8-dihydro-2′-deoxyguanosine in cellular DNA: a validation study. Free Radic Res 33: 243–260.

    PubMed  CAS  Google Scholar 

  • Duprat F, Guillemare E, Romey G, et al (1995) Susceptibility of cloned K+ channels to reactive oxygen species. Proc Natl Acad Sci USA 92: 11796–11800.

    PubMed  CAS  Google Scholar 

  • El Kossi MM, Zakhary MM (2000) Oxidative stress in the context of acute cerebrovascular stroke. Stroke 31: 1889–1892.

    PubMed  CAS  Google Scholar 

  • Ercal N, Aykin-Burns N, Gurer-Orhan H, McDonald JD (2002) Oxidative stress in a phenylketonuria animal model. Free Radic Biol Med 32: 906–911.

    PubMed  CAS  Google Scholar 

  • Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11: 81–128.

    PubMed  CAS  Google Scholar 

  • Fairbairn DW, Olive PL, O'Neill KL (1995) The comet assay: a comprehensive review. Mutat Res 339: 35–59.

    Google Scholar 

  • Fighera MR, Queiroz CM, Stracke MP, et al (1999) Ascorbic acid and alpha-tocopherol attenuate methylmalonic acid-induced convulsions. Neuroreport 10: 2039–2043.

    PubMed  CAS  Google Scholar 

  • Fighera MR, Bonini JS, de Oliveira TG, et al (2003) GM1 ganglioside attenuates convulsions and thiobarbituric acid reactive substances production induced by the intrastriatal administration of methylmalonicac id. Int J Biochem Cell Biol 35: 465–473.

    PubMed  CAS  Google Scholar 

  • Flohe L, Gunzler WA, Schock HH (1973) Glutathione peroxidase: a selenoenzyme. FEBS Lett 32: 132–134.

    PubMed  CAS  Google Scholar 

  • Flott-Rahmel B, Falter C, Schluff P, et al (1997) Nerve cell lesions caused by 3-hydroxyglutaric acid: a possible mechanism for neurodegeneration in glutaric acid I. J Inherit Metab Dis 20: 387–390.

    PubMed  CAS  Google Scholar 

  • Fontella FU, Pulrolnik V, Gassen E, et al (2000) Propionic and L-methylmalonic acids induce oxidative stress in brain of young rats. Neuroreport 11: 541–544.

    PubMed  CAS  Google Scholar 

  • Fontella FU, Gassen E, Pulrolnik V, et al (2002) Stimulation of lipid peroxidation in vitro in rat brain by the metabolites accumulating in maple syrup urine disease. Metab Brain Dis 17: 47–54.

    PubMed  CAS  Google Scholar 

  • Forfia PR, Hintze TH, Wolin MS, Kaley G (1999) Role of nitricoxide in the control of mitochondrial function. Adv Exp Med Biol 471: 381–388.

    PubMed  CAS  Google Scholar 

  • Frizzo ME, Schwarzbold C, Porciuncula LO, et al (2004) 3-Hydroxyglutaric acid enhances glutamate uptake into astrocytes from cerebral cortex of young rats. Neurochem Int 44: 345–353.

    PubMed  CAS  Google Scholar 

  • Gassen M, Gross A, Youdim MB (1999) Apomorphine, a dopamine receptor agonist with remarkable antioxidant and cytoprotective properties. Adv Neurol 80: 297–302.

    PubMed  CAS  Google Scholar 

  • Goodman SI, Frerman FE (2001) Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. TheMetabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2195–2204.

    Google Scholar 

  • Gunter TE, Pfeiffer DR (1990) Mechanisms by which mitochondria transport calcium. Am J Physiol 258: 755–786.

    Google Scholar 

  • Gupta M, Hogema BM, Grompe M, et al (2003) Murine succinate semialdehyde dehydrogenase deficiency. Ann Neurol 54: 81–90.

    Google Scholar 

  • Halliwell B (2001) Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging 18: 685–716.

    PubMed  CAS  Google Scholar 

  • Halliwell B (2002) Hypothesis: proteasomal dysfunction: a primary event in neurogeneration that leads to nitrative and oxidative stress and subsequent cell death. Ann NY Acad Sci 962: 182–194.

    Article  PubMed  CAS  Google Scholar 

  • Halliwell B (2003) Oxidative stress in cell culture: an under-appreciated problem FEBS Lett 540: 3–6.

    PubMed  CAS  Google Scholar 

  • Halliwell B and Gutteridge JMC (1999a) Oxidative stress: adaptation, damage, repair and death. In: Halliwell B, Gutteridge JMC, eds. Free Radicals in Biology and Medicine. Oxford: Oxford University Press, 246–350.

    Google Scholar 

  • Halliwell B and Gutteridge JMC (1999b) Antioxidant defences. In: Halliwell B, Gutteridge JMC, eds. Free Radicals in Biology and Medicine. Oxford: Oxford University Press, 105–245.

    Google Scholar 

  • Heales SJ, Bolanos JP, Brand MP, Clark JB, Land JM (1996) Mitochondrial damage: an important feature in a number of inborn errors of metabolism? J Inherit Metab Dis 19: 140–142.

    PubMed  CAS  Google Scholar 

  • Hilt W, Wolf DH (1996) Proteasomes: destruction as a programme. Trends Biochem Sci 21: 96–102.

    PubMed  CAS  Google Scholar 

  • Hoffmann GF (1994) Selective screening for inborn errors of metabolism: past, present and future. Eur J Pediatr 153: S2.

    PubMed  CAS  Google Scholar 

  • Hoffmann GF, Zschocke J (1999) Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis 22: 381–391.

    PubMed  CAS  Google Scholar 

  • Hoffmann GF, Gibson KM, Trefz FK, Nyhan WL, Bremer HJ, Rating D (1994) Neurological manifestations of organicac id disorders. Eur J Pediatr 153: 94–100.

    Google Scholar 

  • Huttenlocher PR (2000) The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 159: 102–106.

    Google Scholar 

  • Ischiropoulos H (1998) Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys 356: 1–11.

    PubMed  CAS  Google Scholar 

  • Jenner P (2003) Oxidative stress in Parkinson's disease. AnnNeurol 53: 26–36; discussion 36-38.

    Google Scholar 

  • Jenner P, Olanow CW (1996) Oxidative stress and the pathogenesis of Parkinson's disease. Neurology 47: 161–170.

    Google Scholar 

  • Jouvet P, Rustin P, Taylor DL, et al (2000) Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell 11: 1919–1932.

    PubMed  CAS  Google Scholar 

  • Junqueira D, Brusque AM, Porciuncula LO, et al (2003) Effects of L-2-hydroxyglutaric acid on various parameters of the glutamatergic system in cerebral cortex of rats. Metab Brain Dis 18: 233–243.

    PubMed  CAS  Google Scholar 

  • Junqueira D, Brusque AM, Porciuncula LO, et al (2004) In vitro effects of 2-hydroxyglutaric acid on glutamate binding, uptake and release in cerebral cortex of rats. J Neurol Sci 217: 189–194.

    PubMed  CAS  Google Scholar 

  • Kaneko T, Tahara S, Matsuo M (1996) Non-linear accumulation of 8-hydroxy-20-deoxyguanosine, an oxidized DNA damage, during aging. Mutat Res 316: 277–285.

    PubMed  CAS  Google Scholar 

  • Karlhuber GM, Bauer HC, Eckl PM (1997) Cytotoxic and genotoxic effects of 4-hydroxynonenal in cerebral endothelial cells. Mutat Res 381: 209–216.

    PubMed  CAS  Google Scholar 

  • Keller JN, Hanni KB, Markesbery WR (1999) 4-Hydroxynonenal increases neuronal susceptibility to oxidative stress. J Neurosci Res 58: 823–830.

    PubMed  CAS  Google Scholar 

  • Kienzle Hagen ME, Pederzolli CD, Sgaravatti AM, et al (2002) Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim Biophys Acta 1586: 344–352.

    PubMed  CAS  Google Scholar 

  • Klose DA, Kölker S, Heinrich B, et al (2002) Incidence and short-term outcome of children with symptomatic presentation of organic acid and fatty acid oxidation disorders in Germany. Pediatrics 110: 1204–1211.

    PubMed  Google Scholar 

  • Koeller DM, Woontner M, Crnic LS, et al (2002) Biochemical, pathologic and behavioral analysis of a mouse model of glutaricac iduria type I. Hum Mol Genet 11: 347–357.

    PubMed  CAS  Google Scholar 

  • Kölker S, Ahlemeyer B, Krieglstein J, Hoffmann GF (1999) 3-Hydroxyglutaricand glutaric acids are neurotoxic through NMDA receptors in vitro. J Inherit Metab Dis 22: 259–262.

    PubMed  Google Scholar 

  • Kölker S, Ahlemeyer B, Krieglstein J, Hoffmann GF (2001a) Contribution of reactive oxygen species to 3-hydroxyglutarate neurotoxicity in primary neuronal cultures from chick embryo telencephalons. Pediatr Res 50: 76–82.

    PubMed  Google Scholar 

  • Kölker S, Ahlemeyer B, Huhne R, Mayatepek E, Krieglstein J, Hoffmann GF (2001b) Potentiation of 3-hydroxyglutarate neurotoxicity following induction of astrocytic iNOS in neonatal rat hippocampal cultures. Eur J Neurosci 13: 2115–2122.

    PubMed  Google Scholar 

  • Kölker S, Mayatepek E, Hoffmann GF (2002a) White matter disease in cerebral organic acid disorders: clinical implications and suggested pathomechanisms. Neuropediatrics 33: 225–231.

    PubMed  Google Scholar 

  • Kölker S, Okun JG, Ahlemeyer B, et al (2002b) Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons. J Neurosci Res 68: 424–431.

    PubMed  Google Scholar 

  • Kölker S, Pawlak V, Ahlemeyer B, et al (2002c) NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in D-2-hydroxyglutaric aciduria. Eur J Neurosci 16: 21–28.

    PubMed  Google Scholar 

  • Kölker S, Kohr G, Ahlemeyer B, (2002d) Ca2+ and Na+ dependence of 3-hydroxyglutarateinduced excitotoxicity in primary neuronal cultures from chick embryo telencephalons. Pediatr Res 52: 199–206.

    PubMed  Google Scholar 

  • Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495: 12–15.

    PubMed  CAS  Google Scholar 

  • Larsson A, Anderson ME (2001) Glutathione synthetase deficiency and other disorders of the g-glutamyl cycle. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. New York: McGraw-Hill, 2205–2216.

    Google Scholar 

  • Latini A, Borba Rosa R, Scussiato K, Llesuy S, Bello-Klein A, Wajner M (2002) 3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defences in cerebral cortex of young rats. Brain Res 956: 367–373.

    PubMed  CAS  Google Scholar 

  • Latini A, Scussiato K, Rosa RB, et al (2003a) Induction of oxidative stress by L-2-hydroxyglutaricac id in rat brain. J Neurosci Res 74: 103–110.

    PubMed  CAS  Google Scholar 

  • Latini A, Scussiato K, Rosa RB, et al (2003b) D-2-Hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats. Eur J Neurosci 17: 2017–2022.

    PubMed  Google Scholar 

  • Leipnitz G, Schuck PF, Ribeiro CA, et al (2003) Ethylmalonic acid inhibits mitochondrial creatine kinase activity from cerebral cortex of young rats in vitro. Neurochem Res 28: 771–777.

    PubMed  CAS  Google Scholar 

  • Leist M, Single B, Naumann H, et al (1999) Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis. Exp Cell Res 249: 396–403.

    PubMed  CAS  Google Scholar 

  • Levine RL (2001) Carbonyl modified proteins in cellular regulation, aging, and disease. Free Radic Biol Med 32: 790–796.

    Google Scholar 

  • Lima TT, Begnini J, de Bastiani J, et al (1998) Pharmacological evidence for GABAergic and glutamatergic involvement in the convulsant and behavioral effects of glutaric acid. Brain Res 802: 55–60.

    PubMed  CAS  Google Scholar 

  • Liochev SL (1996) The role of iron-sulfur clusters in in vivo hydroxyl radical production. Free Radic Res 25: 369–384.

    PubMed  CAS  Google Scholar 

  • Lissi E, Salim-Hanna M, Pascual C, Del Castillo MD (1995) Evaluation of total antioxidant potential (TRAP) and total antioxidant reactivity from luminol-enhanced chemiluminescence measurements. Free Radic Biol Med 18: 153–158.

    PubMed  CAS  Google Scholar 

  • Liu D, Wen J, Liu J, Li L (1999) The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. FASEB J 13: 2318–2328.

    PubMed  CAS  Google Scholar 

  • Lonnrot K, Metsa-Ketela T, Molnar G, et al (1996) The effect of ascorbic acid and ubiquinone supplementation on plasma and CSF total antioxidant capacity. Free Radic Biol Med 21: 211–217.

    PubMed  CAS  Google Scholar 

  • Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP (1997) A role for 4-hydroxynonenal, an aldehydicproduc t of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J Neurochem 68: 255–264.

    Article  PubMed  CAS  Google Scholar 

  • Mates JM, Pérez-Gómez C, Núñez de Castro I (1999) Antioxidant enzymes and human diseases. Clin Biochem 32: 595–603.

    PubMed  CAS  Google Scholar 

  • McDonald JW, Behrens MI, Chung C, Bhattacharyya T, Choi DW (1997) Susceptibility to apoptosis is enhanced in immature cortical neurons. Brain Res 759: 228–232.

    PubMed  CAS  Google Scholar 

  • McConnell EJ, Bittelmeyer AM, Raess BU (1999) Irreversible inhibition of plasma membrane (Ca2+Mg2+)-ATPase and Ca2+ transport by 4-OH-2,3-trans-nonenal. Arch Biochem Biophys 361: 252–256.

    PubMed  CAS  Google Scholar 

  • Meister A (1975) Metabolism of sulfur compounds. In: Greenberg DM, ed. Metabolic Pathways. New York, Academic Press, 102–188.

    Google Scholar 

  • Melino G, Bernassola F, Knight RA, Corasaniti MT, Nistico G, Finazzi-Agro A (1997) S-Nitrosylation regulates apoptosis. Nature 388: 432–433.

    PubMed  CAS  Google Scholar 

  • Miyazaki T, Ohura T, Kobayashi M, et al (2001) Fatal propionic aciduria in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene. J Biol Chem 276: 35995–35999.

    PubMed  CAS  Google Scholar 

  • Moncada S, Higgs A (1993) The L-arginine-nitricoxide pathway. N Engl J Med 329: 2002–2012.

    PubMed  CAS  Google Scholar 

  • Moyano D, Vilaseca MA, Pineda M, et al (1997) Tocopherol in inborn errors of intermediary metabolism. Clin Chim Acta 263: 147–155.

    PubMed  CAS  Google Scholar 

  • Ong WY, Lu XR, Hu CY, Halliwell B (2000) Distribution of hydroxynonenal-modified proteins in the kainate-lesioned rat hippocampus: evidence that hydroxynonenal formation precedes neuronal cell death. Free Radic Biol Med 28: 1214–1221.

    PubMed  CAS  Google Scholar 

  • Perry G, Taddeo MA, Petersen RB, et al (2003) Oxidative damage in Alzheimer disease. Biometals 16: 77–81.

    PubMed  CAS  Google Scholar 

  • Peters H, Nefedov M, Sarsero J, et al (2003) A knockout mouse model for methylmalonic aciduria resulting in neonatal lethality. J Biol Chem 278: 52909–52913.

    PubMed  CAS  Google Scholar 

  • Pettenuzzo LF, Schuck PF, Fontella F, et al (2002) Ascorbic acid prevents cognitive deficits caused by chronic administration of propionic acid to rats in the water maze. Pharmacol Biochem Behav 73: 623–629.

    PubMed  CAS  Google Scholar 

  • Pettenuzzo LF, Schuck PF, Wyse AT, et al (2003) Ascorbic acid prevents water maze behavioral deficits caused by early postnatal methylmalonic acid administration in the rat. Brain Res 976: 234–242.

    PubMed  CAS  Google Scholar 

  • Porciuncula LO, Dal-Pizzol A Jr, Coitinho AS, Emanuelli T, Souza DO, Wajner M (2000) Inhibition of synaptosomal [3H]glutamate uptake and [3H]glutamate binding to plasma membranes from brain of young rats by glutaricac id in vitro. J Neurol Sci 173: 93–96.

    PubMed  CAS  Google Scholar 

  • Radi R, Rodriguez M, Castro L, Telleri R (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308: 89–95.

    PubMed  CAS  Google Scholar 

  • Radi R, Cassina A, Hodara R (2002) Nitricoxide and peroxynitrite interactions with mitochondria. Biol Chem 383: 401–409.

    PubMed  CAS  Google Scholar 

  • Richter C (1987) Biophysical consequences of lipid peroxidation in membranes. Chem Phys Lipids 44: 175–189.

    PubMed  CAS  Google Scholar 

  • Riobo NA, Melani M, Sanjuan N, et al (2002) The modulation of mitochondrial nitric-oxide synthase activity in rat brain development. J Biol Chem 277: 42447–42455.

    PubMed  CAS  Google Scholar 

  • Schapira AH (2002) Primary and secondary defects of the mitochondrial respiratory chain. J Inherit Metab Dis 25: 207–214.

    PubMed  CAS  Google Scholar 

  • Sgaravatti AM, Rosa RB, Schuck PF, et al (2003) Inhibition of brain energy metabolism by the alpha-keto acids accumulating in maple syrup urine disease. Biochim Biophys Acta 1639: 232–238.

    PubMed  CAS  Google Scholar 

  • Sierra C, Vilaseca MA, Brandi N et al (2001) Oxidative stress in Rett syndrome. Brain Dev 23(suppl.1):S236–S239.

    PubMed  Google Scholar 

  • Sies H (1985) Oxidative stress: introductory remarks. In: Sies H, ed. Oxidative Stress. London: Academic Press.

    Google Scholar 

  • Silva AR, Ruschel C, Helegda C, et al (1999) Inhibition of rat brain lipid synthesis in vitro by 4-hydroxybutyricac id. Metab Brain Dis 14: 157–164.

    PubMed  CAS  Google Scholar 

  • Silva CG, Silva AR, Ruschel C, et al (2000) Inhibition of energy production in vitro by glutaric acid in cerebral cortex of young rats. Metab Brain Dis 15: 123–131.

    PubMed  CAS  Google Scholar 

  • Silva AR, Ruschel C, Helegda C, et al (2001) Inhibition of in vitro CO2 production and lipid synthesis by 2-hydroxybutyricac id in rat brain. Braz J Med Biol Res 34: 627–631.

    PubMed  CAS  Google Scholar 

  • Slater AF, Stefan C, Novel I, van den Dobbelsteen DJ, Orrenius S (1995) Signalling mechanisms and oxidative stress in apoptosis. Toxicol Lett 82-83: 149–153.

    PubMed  CAS  Google Scholar 

  • Sousa SC, Maciel EN, Vercesi AE, Castilho RF (2003) Ca2+-induced oxidative stress in brain mitochondria treated with the respiratory chain inhibitor rotenone. FEBS Lett 543: 179–183.

    PubMed  CAS  Google Scholar 

  • Stokes AH, Hastings TG, Vrana KE (1999) Cytotoxicand genotoxicpotential of dopamine. Ann NY Acad Sci 899: 191–208.

    Google Scholar 

  • Strauss KA, Morton DH (2003) Type I glutaric aciduria, part 2: a model of acute striatal necrosis. Am J Med Genet 121: 53–70.

    Google Scholar 

  • Strauss KA, Puffenberger EG, Robinson DL, Morton DH (2003) Type I glutaricac iduria, part 1: natural history of 77 patients. Am J Med Genet 121: 38–52.

    Google Scholar 

  • Streck EL, Zugno AI, Tagliari B, et al (2001) Inhibition of rat brain Na+,K+-ATPase activity induced by homocysteine is probably mediated by oxidative stress. Neurochem Res 26: 1195–1200.

    PubMed  CAS  Google Scholar 

  • Streck EL, Vieira PS, Wannmacher CM, Dutra-Filho CS, Wajner M, Wyse AT (2003) In vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampus. Metab Brain Dis 18: 147–154.

    PubMed  CAS  Google Scholar 

  • Subramaniam R, Koppal T, Green M, et al (1998) The free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid beta-peptide(25-35) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimer's disease. Neurochem Res 23: 1403–1410.

    PubMed  CAS  Google Scholar 

  • Surendran S, Matalon KM, Szucs S, Tyring SK, Matalon R (2003) Metabolic changes in the knockout mouse for Canavan's disease: implications for patients with Canavan's disease. J Child Neurol 18: 611–615.

    PubMed  Google Scholar 

  • Sweetman L (1991) Organicac id analysis. In: Hommes FA, ed. Techniques in Diagnostic Human Biochemical Genetics: A Laboratory Manual. New York: Wiley-Liss, 143–176.

    Google Scholar 

  • Tavares RG, Santos CE, Tasca CI, Wajner M, Souza DO, Dutra-Filho CS (2000) Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease. J Neurol Sci 181: 44–49.

    PubMed  CAS  Google Scholar 

  • Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C (2002) Biochemical markers related to Alzheimer's dementia in serum and cerebrospinal fluid. Neurobiol Aging 23: 485–508.

    PubMed  CAS  Google Scholar 

  • Thomas PD, Poznansky MJ (1990) Lipid peroxidation inactivates rat liver microsomal glycerol-3-phosphate acyl transferase. Effect of iron and copper salts and carbon tetrachloride. J Biol Chem 265: 2684–2691.

    PubMed  CAS  Google Scholar 

  • Ullrich K, Flott-Rahmel B, Schluff P, et al (1999) Glutaric aciduria type I: pathomechanisms of neurodegeneration. J Inherit Metab Dis 22: 392–403.

    PubMed  CAS  Google Scholar 

  • van den Dobbelsteen DJ, Nobel CS, Schlegel J, Cotgreave IA, Orrenius S, Slater AF (1996) Rapid and specific efflux of reduced glutathione during apoptosis induced by anti-Fas/APO-1 antibody. J Biol Chem 271: 15420–15427.

    PubMed  CAS  Google Scholar 

  • Vargas CR, Wajner M, Sirtori LR, et al (2004) Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy. Biochim Biophys Acta 1688: 26–32.

    PubMed  CAS  Google Scholar 

  • Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J Neurosci 14: 2924–2932.

    PubMed  CAS  Google Scholar 

  • Wajner M, Coelho JC (1997) Neurological dysfunction in methylmalonic aciduria is probably related to the inhibitory effect of methylmalonate on brain energy production. J Inherit Metab Dis 20: 761–768.

    PubMed  CAS  Google Scholar 

  • Wallace DC (2002) Animal models for mitochondrial disease. Methods Mol Biol 197: 3–54.

    PubMed  CAS  Google Scholar 

  • Wen GY, Wisniewski HM, Shek JW, Loo YH, Fulton TR (1980) Neuropathology of phenylacetate poisoning in rats: an experimental model of phenylketonuria. Ann Neurol 7: 557–566.

    PubMed  CAS  Google Scholar 

  • Wyse AT, Streck EL, Barros SV, Brusque AM, Zugno AI, Wajner M (2000) Methylmalonate administration decreases Na+,K+-ATPase activity in cerebral cortex of rats. Neuroreport 11: 2331–2334.

    PubMed  CAS  Google Scholar 

  • Wyse AT, Bavaresco CS, Bandinelli C, et al (2001) NOS inhibition by L-NAME prevents the decrease of Na+,K+-ATPase activity in midbrain of rats subjected to arginine administration. Neurochem Res 26: 515–520.

    PubMed  CAS  Google Scholar 

  • Wyse AT, Zugno AI, Streck EL, et al (2002) Inhibition of Na+,K+-ATPase activity in hippocampus of rats subjected to acute administration of homocysteine is prevented by vitamins E and C treatment. Neurochem Res 27: 1685–1689.

    PubMed  CAS  Google Scholar 

  • Zaleska MM, Floyd RA (1985) Regional lipid peroxidation in rat brain in vitro: possible role of endogenous iron. Neurochem Res 10: 397–410.

    PubMed  CAS  Google Scholar 

  • Zeevalk GD, Nicklas WJ (1992) Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-D-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J Neurochem 59: 1211–1220.

    PubMed  CAS  Google Scholar 

  • Zugno AI, Stefanello FM, Streck EL, et al (2003) Inhibition of Na+,K+-ATPase activity in rat striatum by guanidinoacetate. Int J Dev Neurosci 21: 183–189.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS

    M. Wajner

  2. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS

    M. Wajner, A. Latini, A. T. S. Wyse & C. S. Dutra-Filho

  3. Universidade Luterana do Brasil, Canoas, RS, Brazil

    M. Wajner

  4. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS

    A. Latini

Authors
  1. M. Wajner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Latini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. T. S. Wyse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. S. Dutra-Filho
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wajner, M., Latini, A., Wyse, A.T.S. et al. The role of oxidative damage in the neuropathology of organic acidurias: Insights from animal studies. J Inherit Metab Dis 27, 427–448 (2004). https://doi.org/10.1023/B:BOLI.0000037353.13085.e2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BOLI.0000037353.13085.e2

Keywords

Search

Navigation