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L-carnitine Prevents Oxidative Stress in the Brains of Rats Subjected to a Chemically Induced Chronic Model of MSUD

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Abstract

Maple syrup urine disease (MSUD), or branched-chain α-keto aciduria, is an inherited disorder that is caused by a deficiency in branched-chain α-keto acid dehydrogenase complex (BCKAD) activity. Blockade of this pathway leads to the accumulation of the branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, and their respective ketoacids in tissues. The main clinical symptoms presented by MSUD patients include ketoacidosis, hypoglycemia, opisthotonos, poor feeding, apnea, ataxia, convulsions, coma, psychomotor delay, and mental retardation. Although increasing evidence indicates that oxidative stress is involved in the pathophysiology of this disease, the mechanisms of the brain damage caused by this disorder remain poorly understood. In the present study, we investigated the effect of BCAAs on some oxidative stress parameters and evaluated the efficacy of L-carnitine (L-car), an efficient antioxidant that may be involved in the reduction of oxidative damage observed in some inherited neurometabolic diseases, against these possible pro-oxidant effects of a chronic MSUD model in the cerebral cortex and cerebellum of rats. Our results showed that chronic BCAA administration was able to promote both lipid and protein oxidation, impair brain antioxidant defenses, and increase reactive species production, particularly in the cerebral cortex, and that L-car was able to prevent these effects. Taken together, the present data indicate that chronic BCAA administration significantly increased oxidative damage in the brains of rats subjected to a chronic model of MSUD and that L-car may be an efficient antioxidant in this disorder.

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References

  1. Chuang DT, Shih VE (2001) Maple syrup urine disease (branched chain ketoaciduria). In: Scriver CR, Beaudt AL, Sly WL, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1971–2005

    Google Scholar 

  2. Chuang DT, Chuang JL, Wynn RM (2006) Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr 136:243S–249S

    CAS  PubMed  Google Scholar 

  3. Schönberger S, Schweiger B, Schwahn B, Schwarz M, Wendel U (2004) Dysmyelination in the brain of adolescents and young adults with maple syrup urine disease. Mol Genet Metab 82:69–75

    Article  PubMed  Google Scholar 

  4. Hoffmann B, Helbling C, Schadewaldt P, Wendel U (2006) Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD. Pediatr Res 59:17–20

    Article  CAS  PubMed  Google Scholar 

  5. Klee D, Thimm E, Wittsack HJ, Schubert D, Primke R, Pentang G, Schaper J, Mödder U et al (2013) Structural white matter changes in adolescents and young adults with maple syrup urine disease. J Inherit Metab Dis 36:945–953

    Article  CAS  PubMed  Google Scholar 

  6. Araújo P, Wassermann GF, Tallini K, Furlanetto V, Vargas CR, Wannmacher CMD, Dutra-Filho CS, Wyse ATS et al (2001) Reduction of large neutral amino acid level in plasma and brain of hyperleucinemic rats. Neurochem Int 38:529–537

    Article  PubMed  Google Scholar 

  7. Pilla C, Cardozo RFD, Dutra CS, Wyze ATS, Wajner M, Wannmacher CMD (2003) Effect of leucine administration on creatine kinase activity in rat brain. Metab Brain Dis 18:17–25

    Article  CAS  PubMed  Google Scholar 

  8. Ribeiro CA, Sgaravatti AM, Rosa RB, Schuck PF, Grando V, Schmidt AL, Ferreira GC, Perry MLS et al (2008) Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Int 33:114–124

    Article  CAS  Google Scholar 

  9. Jouvet P, Rustin P, Taylor DL, Pocock JM, Felderhoff-Mueser U, Mazarakis ND, Sarraf C, Joashi U et al (2000) Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane despolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell 11:1919–1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Treacy E, Clow CL, Reade TR, Chitayat D, Mamer OA, Scriver CR (1992) Maple syrup urine disease: interrelationship between branched chain amino-, oxo- and hydroxylacids implications for treatment association with CNS dysmyelination. J Inherit Metab Dis 15:121–135

    Article  CAS  PubMed  Google Scholar 

  11. Barschak AG, Sitta A, Deon M, Oliveira MH, Haeser A, Dutra-Filho CS, Wajner M, Vargas CR (2006) Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease. Metab Brain Dis 21:279–286

    Article  CAS  PubMed  Google Scholar 

  12. Barschak AG, Sitta A, Deon M, Barden AT, Dutra-Filho CS, Wajner M, Vargas CR (2008) Oxidative stress in plasma from maple syrup urine disease patients during treatment. Metab Brain Dis 23:71–80

    Article  CAS  PubMed  Google Scholar 

  13. Bridi R, Araldi J, Sgarbi MB, Testa CG, Durigon K, Wajner M, Dutra-Filho CS (2003) Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. Int J Dev Neurosci 21:327–332

    Article  CAS  PubMed  Google Scholar 

  14. Bridi R, Braum CA, Zorzi GK, Wannmacher CM, Wajner M, Lissi EG, Dutra-Filho CS (2005) Alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defenses in cerebral cortex from young rats. Metab Brain Dis 20:155–167

    Article  CAS  PubMed  Google Scholar 

  15. Bridi R, Latini A, Braum CA, Zorzi GK, Moacir W, Lissi E, Dutra-Filho CS (2005) Evaluation of the mechanism involved in leucine-induced oxidative damage in cerebral cortex of young rats. Free Radic Res 39:71–79

    Article  CAS  PubMed  Google Scholar 

  16. Fontella FU, Gassen E, Pulrolnik V, Wannmacher CMD, Klein AB, Wajner M, Dutra CS (2002) Stimulation of lipid peroxidation in vitro in rat brain by metabolites accumulating in maple syrup urine disease. Metab Brain Dis 17:47–54

    Article  CAS  PubMed  Google Scholar 

  17. Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A et al (2014) Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Mol Genet Metab 112:210–217

    Article  CAS  PubMed  Google Scholar 

  18. Barschak AG, Sitta A, Deon M, Barden AT, Schmitt GO, Dutra-Filho CS, Wajner M, Vargas CR (2007) Erythrocyte glutathione peroxidase activity and plasma selenium concentration are reduced in maple syrup urine disease patients during treatment. Int J Dev Neurosci 25:335–338

    Article  CAS  PubMed  Google Scholar 

  19. Gulcin I (2006) Antioxidant and antiradical activities of L-carnitine. Life Sci 78:803–811

    Article  PubMed  Google Scholar 

  20. Mescka CP, Wayhs CA, Vanzin CS, Biancini GB, Guerreiro G, Manfredini V, Souza C, Wajner M et al (2013) Protein and lipid damage in maple syrup urine disease patients: L-carnitine effect. Int J Dev Neurosci 31:21–24

    Article  CAS  PubMed  Google Scholar 

  21. Abdul HM, Butterfield DA (2007) Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Free Radic Biol Med 42:371–384

    Article  PubMed  Google Scholar 

  22. Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ribas GS, Vargas CR, Wajner M (2014) L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 533:469–476

    Article  CAS  PubMed  Google Scholar 

  24. Mescka C, Moraes T, Rosa A, Mazzola P, Piccoli B, Jacques C, Dalazen G, Coelho J et al (2011) In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease. Metab Brain Dis 26:21–28

    Article  CAS  PubMed  Google Scholar 

  25. Bridi R, Fontella FU, Pulrolnik V, Braun C, Zorzi GK, Coelho D, Wajner M, Vargas CR et al (2006) A chemically induced acute model of maple syrup urine disease in rats for neurochemical studies. J Neurosci Methods 155:224–230

    Article  CAS  PubMed  Google Scholar 

  26. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  27. Reznick AZ, Packer L (1994) Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 233:357–363

    Article  CAS  PubMed  Google Scholar 

  28. Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Enzymol 108:347–352

    CAS  Google Scholar 

  29. Lebel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231

    Article  CAS  PubMed  Google Scholar 

  30. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  31. Marklund SL (1985) Pyrogallol autoxidation. In: Greenwald RA (ed) Handbook of methods for oxygen radical research. CRC Press, Boca Raton, pp 243–247

    Google Scholar 

  32. Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333

    Article  CAS  PubMed  Google Scholar 

  33. Leong SF, Clark JB (1984) Regional enzyme development in rat brain. Enzymes associated with glucose utilization. Biochem J 218:131–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Joseph MH, Marsden CA (1986) Amino acids and small peptides. In: Lim CF (ed) HPLC of small peptides. IRL Press, Oxford, pp 13–27

    Google Scholar 

  35. De Sousa C, English NR, Stacey TE, Chalmers RA (1990) Measurement of L-carnitine and acylcarnitines in body fluids and tissues in children and in adults. Clin Chim Acta 187:317–328

    Article  PubMed  Google Scholar 

  36. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  37. Danner DJ, Elsas JL (1989) Disorders of branched chain amino acid and keto acid metabolism. In: Scriver CR, Beaudt AL, Sly WL, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 671–692

    Google Scholar 

  38. Funchal C, Latini A, Jacques-Silva MC, Dos Santos AQ, Buzin L, Gottfried C, Wajner M, Pessoa-Pureur R (2006) Morphological alterations and induction of oxidative stress in glial cells caused by branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int 49:640–650

    Article  CAS  PubMed  Google Scholar 

  39. de Lima PP, Funchal C, Loureiro SO, Heimfarth L, Zamoner A, Gottfried C, Latini A, Wajner M et al (2007) Branched-chain amino acids accumulating in maple syrup urine disease induce morphological alterations in C6 glioma cells probably through reactive species. Int J Dev Neurosci 25:181–189

    Article  Google Scholar 

  40. Sitta A, Ribas GS, Mescka CP, Barschak AG, Wajner M, Vargas CR (2014) Neurological damage in MSUD: the role of oxidative stress. Cell Mol Neurobiol 34:157–165

    Article  CAS  PubMed  Google Scholar 

  41. Mescka CP, Wayhs CA, Guerreiro G, Manfredini V, Dutra-Filho CS, Vargas CR (2014) Prevention of DNA damage by L-carnitine induced by metabolites accumulated in maple syrup urine disease in human peripheral leukocytes in vitro. Gene 548:294–298

    Article  CAS  PubMed  Google Scholar 

  42. Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI (2002) Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 109:999–1008

    Article  PubMed  Google Scholar 

  43. Rani PJ, Panneerselvam C (2002) Effect of L-carnitine on brain lipid peroxidation and antioxidant enzymes in old rats. J Gerontol A Biol Sci Med Sci 57:B134–B137

    Article  PubMed  Google Scholar 

  44. Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A (2003) Protein carbonylation in human diseases. Trends Mol Med 9:169–176

    Article  CAS  PubMed  Google Scholar 

  45. Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A (2006) Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med 10:389–406

    Article  CAS  PubMed  Google Scholar 

  46. Gemelli T, de Andrade RB, Rojas DB, Bonorino NF, Mazzola PN, Tortorelli LS, Funchal C, Filho CS et al (2013) Effects of β-alanine administration on selected parameters of oxidative stress and phosphoryltransfer network in cerebral cortex and cerebellum of rats. Mol Cell Biochem 380:161–170

    Article  CAS  PubMed  Google Scholar 

  47. Rojas DB, Gemelli T, de Andrade RB, Campos AG, Dutra-Filho CS, Wannmacher CM (2012) Administration of histidine to female rats induces changes in oxidative status in cortex and hippocampus of the offspring. Neurochem Res 37:1031–1036

    Article  CAS  PubMed  Google Scholar 

  48. Moraes TB, Zanin F, da Rosa A, de Oliveira A, Coelho J, Petrillo F, Wajner M, Dutra-Filho CS (2010) Lipoic acid prevents oxidative stress in vitro and in vivo by an acute hyperphenylalaninemia chemically-induced in rat brain. J Neurol Sci 292:89–95

    Article  CAS  PubMed  Google Scholar 

  49. Lushchak VI (2014) Free radicals, reactive oxygen species, oxidative stress and its classification. Chem Biol Interact 224C:164–175

    Article  Google Scholar 

  50. Lipinski B (2012) Hydroxyl radical and its scavengers in health and disease. Oxidative Med Cell Longev 2012:809696

    Google Scholar 

  51. Li JL, Wang QY, Luan HY, Kang ZC, Wang CB (2012) Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha. J Biomed Sci 21:19–32

    Google Scholar 

  52. Ye J, Li J, Yu Y, Wei Q, Deng W, Yu L (2010) L-carnitine attenuates oxidant injury in HK-2 cells via ROS-mitochondria pathway. Regul Pept 161:58–66

    Article  CAS  PubMed  Google Scholar 

  53. Ho HY, Cheng ML, Chiu DT (2007) Glucose-6-phosphate dehydrogenase-from oxidative stress to cellular functions and degenerative diseases. Redox Rep 12:109–118

    Article  CAS  PubMed  Google Scholar 

  54. Pederzolli CD, Mescka CP, Zandoná BR, de Moura CD, Sgaravatti AM, Sgarbi MB, de Souza Wyse AT, Duval Wannmacher CM et al (2010) Acute administration of 5-oxoproline induces oxidative damage to lipids and proteins and impairs antioxidant defenses in cerebral cortex and cerebellum of young rats. Metab Brain 25:145–154

    Article  CAS  Google Scholar 

  55. Ninfali P, Ditroilo M, Capellacci S, Biagiotti E (2001) Rabbit brain glucose-6-phosphate dehydrogenase: biochemical properties and inactivation by free radicals and 4-hydroxy-2-nonenal. Neuroreport 12:4149–4153

    Article  CAS  PubMed  Google Scholar 

  56. Yang MS, Chan HW, Yu LC (2006) Glutathione peroxidase and glutathione reductase activities are partially responsible for determining the susceptibility of cells to oxidative stress. Toxicology 226:126–130

    Article  CAS  PubMed  Google Scholar 

  57. Campese VM, Sindhu RK, Ye S, Bay Y, Vaziri ND, Jabbari B (2007) Regional expression of NO synthase, NAD(P)H oxidase and superoxide dismutase in the rat brain. Brain Res 1134:27–32

    Article  CAS  PubMed  Google Scholar 

  58. Beard JL, Connor JR, Jones BC (1993) Iron in the brain. Nutr Rev 51:157–170

    Article  CAS  PubMed  Google Scholar 

  59. Jones LL, McDonald DA, Borum PR (2010) Acylcarnitines: role in brain. Prog Lipid Res 49:61–75

    Article  CAS  PubMed  Google Scholar 

  60. Mc Guire PJ, Parikh A, Diaz GA (2009) Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab 98:173–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by research grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).

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Authors and Affiliations

  1. Departamento de Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600, Porto Alegre, 90035-000, Rio Grande do Sul, Brazil

    Gabriel Schirmbeck, Thales Hein da Rosa, Felipe Catarino, Laila Oliveira de Souza & Carlos Severo Dutra-Filho

  2. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Rua Ramiro Barcelos, 2600, 90035-000, Porto Alegre, Rio Grande do Sul, Brazil

    Caroline Paula Mescka, Andrea Pereira Rosa, Carmen Regla Vargas & Carlos Severo Dutra-Filho

  3. Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Av. Ipiranga, 2752, Porto Alegre, 90610-000, Rio Grande do Sul, Brazil

    Gilian Guerreiro & Carmen Regla Vargas

  4. Serviço de Genética Médica, HCPA, UFRGS, Rua Ramiro Barcelos, 2350, 90035-903, Porto Alegre, Rio Grande do Sul, Brazil

    Caroline Paula Mescka, Gilian Guerreiro, Angela Sitta & Carmen Regla Vargas

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  1. Caroline Paula Mescka
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  2. Andrea Pereira Rosa
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  3. Gabriel Schirmbeck
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  10. Carlos Severo Dutra-Filho
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Correspondence to Carlos Severo Dutra-Filho.

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Mescka, C.P., Rosa, A.P., Schirmbeck, G. et al. L-carnitine Prevents Oxidative Stress in the Brains of Rats Subjected to a Chemically Induced Chronic Model of MSUD. Mol Neurobiol 53, 6007–6017 (2016). https://doi.org/10.1007/s12035-015-9500-z

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