Advertisement

Neurochemical Research

, Volume 40, Issue 5, pp 885–893 | Cite as

Acute Administration of Branched-Chain Amino Acids Increases the Pro-BDNF/Total-BDNF Ratio in the Rat Brain

  • Giselli Scaini
  • Meline O. S. Morais
  • Camila B. Furlanetto
  • Luiza W. Kist
  • Talita C. B. Pereira
  • Patrícia F. Schuck
  • Gustavo C. Ferreira
  • Matheus A. B. Pasquali
  • Daniel P. Gelain
  • José Cláudio F. Moreira
  • Maurício R. Bogo
  • Emilio L. StreckEmail author
Original Paper

Abstract

Maple syrup urine disease (MSUD) is caused by an inborn error in metabolism resulting from a deficiency in the branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as their corresponding α-keto acids and α-hydroxy acids. High levels of BCAAs are associated with neurological dysfunction and the role of pro- and mature brain-derived neurotrophic factor (BDNF) in the neurological dysfunction of MSUD is still unclear. Thus, in the present study we investigated the effect of an acute BCAA pool administration on BDNF levels and on the pro-BDNF cleavage-related proteins S100A10 and tissue plasminogen activator (tPA) in rat brains. Our results demonstrated that acute Hyper-BCAA (H-BCAA) exposure during the early postnatal period increases pro-BDNF and total-BDNF levels in the hippocampus and striatum. Moreover, tPA levels were significantly decreased, without modifications in the tPA transcript levels in the hippocampus and striatum. On the other hand, the S100A10 mRNA and S100A10 protein levels were not changed in the hippocampus and striatum. In the 30-day-old rats, we observed increased pro-BDNF, total-BDNF and tPA levels only in the striatum, whereas the tPA and S100A10 mRNA expression and the immunocontent of S100A10 were not altered. In conclusion, we demonstrated that acute H-BCAA administration increases the pro-BDNF/total-BDNF ratio and decreases the tPA levels in animals, suggesting that the BCAA effect may depend, at least in part, on changes in BDNF post-translational processing.

Keywords

Maple syrup urine disease Branched-chain amino acids Brain-derived neurotrophic factor Tissue plasminogen activator, S100A10 

Notes

Acknowledgments

This research was supported by Grants from the Programa de Pós-graduação em Ciências da Saúde—Universidade do Extremo Sul Catarinense (UNESC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

References

  1. 1.
    Treacy E, Clow CL, Reade TR, Chitayat D, Mamer OA, Scriver CR (1992) Maple syrup urine disease: interrelationship between branched-chain amino-, oxo- and hydroxyacids; implications for treatment; associations with CNS dysmyelination. J Inherit Metab Dis 15:121–135CrossRefPubMedGoogle Scholar
  2. 2.
    Chuang DT, Shih VE (2001) Maple syrup urine disease (branched chain ketoaciduria). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1971–2005Google Scholar
  3. 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 82:69–75CrossRefPubMedGoogle Scholar
  4. 4.
    Halestrap AP, Brand MD, Denton RM (1974) Inhibition of mitochondrial pyruvate transport by phenylpyruvate and -ketoisocaproate. Biochem Biophys Acta 367:102–108CrossRefPubMedGoogle Scholar
  5. 5.
    Land JM, Mowbray J, Clark JB (1976) Control of pyruvate and h-hydroxybutyrate utilization in rat brain mitochondria and its relevance to phenylketonuria and maple syrup urine disease. J Neurochem 26:823–830CrossRefPubMedGoogle Scholar
  6. 6.
    Danner DJ, Elsas LJ (1989) Disorders of branched chain amino acid and keto acid metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 671–692Google Scholar
  7. 7.
    Yudkoff M, Daikhin Y, Lin ZP, Nissim I, Stern J, Pleasure D, Nissim I (1994) Interrelationships of leucine and glutamate metabolism in cultured astrocyts. J Neurochem 62:1192–1202CrossRefPubMedGoogle Scholar
  8. 8.
    Zielke HR, Zielke CL, Baab PJ, Collins RM (2002) Large neutral amino acids auto exchange when infused by microdialysis into the rat brain: implications for maple syrup urine disease and phenylketonuria. Neurochem Int 40:347–354CrossRefPubMedGoogle Scholar
  9. 9.
    Pilla C, Cardozo RF, Dornelles PK, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2003) Kinetic studies on the inhibition of creatine kinase activity by branched-chain alpha-amino acids in the brain cortex of rats. Int J Dev Neurosci 21:145–151CrossRefPubMedGoogle Scholar
  10. 10.
    Pilla C, Cardozo RF, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2003) Creatine kinase activity from rat brain is inhibited by branched chain amino acids in vitro. Neurochem Res 28:675–679CrossRefPubMedGoogle Scholar
  11. 11.
    Prensky AL, Moser HW (1967) Changes in the amino acid composition of proteolipids of white matter during maturation of the human nervous system. J Neurochem 14:117–121CrossRefPubMedGoogle Scholar
  12. 12.
    Dodd PR, Williams SH, Gundlach AL, Harper PA, Healy PJ, Dennis JA, Johnston GA (1992) Glutamate and aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. J Neurochem 59:582–590CrossRefPubMedGoogle Scholar
  13. 13.
    Tavares RG, Santos CES, Tasca C, 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 181:44–49CrossRefPubMedGoogle Scholar
  14. 14.
    Araújo P, Wassermann GF, Tallini K, Furlanetto V, Vargas CR, Wannmacher CM, Dutra-Filho CS, Wyse AT, Wajner M (2001) Reduction of large neutral amino acid levels in plasma and brain of hyperleucinemic rats. Neurochem Int 38:529–537CrossRefPubMedGoogle Scholar
  15. 15.
    Jouvet J, Rustin P, Taylor DL, Pocock JM, Felderhoff-Mueser U, Mazarakis ND, Sarraf C, Joashi U, Kozma M, Greenwood K, Edwards AD, Mehmet H (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 11:1919–1932CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Fontella FU, Gassen E, Pulrolnik V, Wannmacher CM, Klein AB, Wajner M, Dutra-Filho CS (2002) Stimulation of lipid peroxidation in vitro in rat brain by the metabolites accumulating in maple syrup urine disease. Metab Brain Dis 17:47–54CrossRefPubMedGoogle Scholar
  17. 17.
    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 21:327–332CrossRefPubMedGoogle Scholar
  18. 18.
    Bridi R, Latini A, Braum CA, Zorzi GK, Moacir W, Lissi E, Dutra-Filho CS (2005) Evaluation of the mechanisms involved in leucine induced oxidative damage in cerebral cortex of young rats. Free Radic Res 39:71–79CrossRefPubMedGoogle Scholar
  19. 19.
    Barschak AG, Sitta A, Deon M, de Oliveira MH, Haeser A, Dutra-Filho CS, Wajner M, Vargas CR (2006) Evidence that oxidative stress in increased in plasma from patients with maple syrup urine disease. Metab Brain Dis 21:279–286CrossRefPubMedGoogle Scholar
  20. 20.
    Mescka C, Moraes T, Rosa A, Mazzola P, Piccoli B, Jacques C, Dalazen G, Coelho J, Cortes M, Terra M, Regla Vargas C, Dutra-Filho CS (2011) In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease. Metab Brain Dis 26:21–28CrossRefPubMedGoogle Scholar
  21. 21.
    Clarke PG (1985) Neuronal death during development in the isthmo-optic nucleus of the chick: sustaining role of afferents from the tectum. J Comp Neurol 234:365–379CrossRefPubMedGoogle Scholar
  22. 22.
    Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14:453–501CrossRefPubMedGoogle Scholar
  23. 23.
    Vicario-Abejon C, Collin C, McKay RD, Segal M (1998) Neurotrophins induce formation of functional excitatory and inhibitory synapses between cultured hippocampal neurons. J Neurosci 18:7256–7271PubMedGoogle Scholar
  24. 24.
    Luikart BW, Nef S, Virmani T, Lush ME, Liu Y, Kavalali ET, Parada LF (2005) TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci 25:3774–3786CrossRefPubMedGoogle Scholar
  25. 25.
    Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642CrossRefPubMedGoogle Scholar
  27. 27.
    Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32CrossRefPubMedGoogle Scholar
  28. 28.
    Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309CrossRefPubMedGoogle Scholar
  29. 29.
    Lu B, Je HS (2003) Neurotrophic regulation of the development and function of the neuromuscular synapses. J Neurocytol 32:931–941CrossRefPubMedGoogle Scholar
  30. 30.
    Bramham CR (2008) Local protein synthesis, actin dynamics and LTP consolidation. Curr. Opin Neuorbiol 18:524–531CrossRefGoogle Scholar
  31. 31.
    McAllister AK, Katz LC, Lo DC (1999) Neurotrophins and synaptic plasticity. Annu Rev Neurosci 22:295–318CrossRefPubMedGoogle Scholar
  32. 32.
    Carvalho AL, Caldeira MV, Santos SD, Duarte CB (2008) Role of the brain-derived neurotrophic factor at glutamatergic synapses. Br J Pharmacol 153:S310–S324CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P (2001) BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411:86–89CrossRefPubMedGoogle Scholar
  34. 34.
    Mossner R, Daniel S, Albert D, Heils A, Okladnova O, Schmitt A, Lesch KP (2000) Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF). Neurochem Int 36:197–202CrossRefPubMedGoogle Scholar
  35. 35.
    Gezen-Ak D, Dursun E, Hanagasi H, Bilgic B, Lohman E, Araz OS, Atasoy IL, Alaylıoğlu M, Önal B, Gürvit H, Yılmazer S (2013) BDNF, TNFalpha, HSP90, CFH, and IL-10 serum levels in patients with early or late onset alzheimer’s disease or mild cognitive impairment. J Alzheimers Dis 37:185–195PubMedGoogle Scholar
  36. 36.
    Peng S, Wuu J, Mufson EJ, Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brainderived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93:1412–1421CrossRefPubMedGoogle Scholar
  37. 37.
    Yu H, Zhang Z, Shi Y, Bai F, Xie C, Qian Y, Yuan Y, Deng L (2008) Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han. J Clin Psychiatry 69:1104–111110CrossRefPubMedGoogle Scholar
  38. 38.
    Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R (2005) Neurotrophin levels in postmortem brains of suicide victims and the effects of ante mortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136:29–37CrossRefPubMedGoogle Scholar
  39. 39.
    Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54:70–75CrossRefPubMedGoogle Scholar
  40. 40.
    Cunha AB, Frey BN, Andreazza AC, Goi JD, Rosa AR, Goncalves CA, Santin A, Kapczinski F (2006) Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett 398:215–219CrossRefPubMedGoogle Scholar
  41. 41.
    Terracciano A, Lobina M, Piras MG, Mulas A, Cannas A, Meirelles O, Sutin AR, Zonderman AB, Uda M, Crisponi L, Schlessinger D (2011) Neuroticism, depressive symptoms, and serum BDNF. Psychosom Med 73:638–642CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69:341–374CrossRefPubMedGoogle Scholar
  43. 43.
    Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brainderived neurotrophic factor. Proc Natl Acad Sci USA 92:8856–8860CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381:706–709CrossRefPubMedGoogle Scholar
  45. 45.
    Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16:1137–1145CrossRefPubMedGoogle Scholar
  46. 46.
    Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6:603–614CrossRefPubMedGoogle Scholar
  47. 47.
    Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948CrossRefPubMedGoogle Scholar
  48. 48.
    Pang PT, Teng HK, Zaitsev E (2004) Cleavage of pro-BDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306:487–491CrossRefPubMedGoogle Scholar
  49. 49.
    Kassam G, Le BH, Choi KS, Kang HM, Fitzpatrick SL, Louie P, Waisman DM (1998) The p11 subunit of the annexin II tetramer plays a key role in the stimulation of t-PA-dependent plasminogen activation. Biochemistry 37:16958–16966CrossRefPubMedGoogle Scholar
  50. 50.
    Zobiack N, Rescher U, Ludwig C, Zeuschner D, Gerke V (2003) The annexin 2/S100A10 complex controls the distribution of transferrin receptor-containing recycling endosomes. Mol Biol Cell 14:4896–4908CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76(2):99–125CrossRefPubMedGoogle Scholar
  52. 52.
    Goldberg TE, Weinberger DR (2004) Genes and the parsing of cognitive processes. Trends Cogn Sci 8:325–335CrossRefGoogle Scholar
  53. 53.
    Scaini G, Teodorak BP, Jeremias IC, Morais MO, Mina F, Dominguini D, Pescador B, Comim CM, Schuck PF, Ferreira GC, Quevedo J, Streck EL (2012) Antioxidant administration prevents memory impairment in an animal model of maple syrup urine disease. Behav Brain Res 231:92–96CrossRefPubMedGoogle Scholar
  54. 54.
    Scaini G, Comim CM, Oliveira GM, Pasquali MA, Quevedo J, Gelain DP, Moreira JC, Schuck PF, Ferreira GC, Bogo MR, Streck EL (2013) Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model. J Inherit Metab Dis 36:721–730CrossRefPubMedGoogle Scholar
  55. 55.
    Glaser V, Carlini VP, Gabach L, Ghersi M, de Barioglio SR, Ramirez OA, Perez MF, Latini A (2010) The intra-hippocampal leucine administration impairs memory consolidation and LTP generation in rats. Cell Mol Neurobiol 30:1067–1075CrossRefPubMedGoogle Scholar
  56. 56.
    VdeC Vasques, Brinco F, Wajner M (2005) Intrahippocampal administration of the branched-chain alpha-hydroxy acids accumulating in maple syrup urine disease compromises rat performance in aversive and non-aversive behavioral tasks. J Neurol Sci 232:11–21CrossRefGoogle Scholar
  57. 57.
    Mello CF, Feksa L, Brusque AM, Wannmacher CM, Wajner M (1999) Chronic early leucine administration induces behavioral deficits in rats. Life Sci 65:747–755CrossRefPubMedGoogle Scholar
  58. 58.
    Bridi R, Fontella FU, Pulrolnik V, Braun CA, Zorzi GK, Coelho D, Wajner M, Vargas CR, Dutra-Filho CS (2006) A chemically-induced acute model of maple syrup urine disease in rats for neurochemical studies. J Neurosci Methods 155:224–230CrossRefPubMedGoogle Scholar
  59. 59.
    Lowry OH, Rosebough NG, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Chem Biol 193:265–275Google Scholar
  60. 60.
    Bonefeld BE, Elfving B, Wegener G (2008) Reference genes for normalization: a study of rat brain tissue. Synapse 62:302–309CrossRefPubMedGoogle Scholar
  61. 61.
    Dimova EY, Samoylenko A, Kietzmann T (2004) Oxidative stress and hypoxia: implications for plasminogen activator inhibitor-1 expression. Antioxid Redox Signal 6:777–791CrossRefPubMedGoogle Scholar
  62. 62.
    Zagotta I, Dimova EY, Funcke JB, Wabitsch M, Kietzmann T, Fischer-Posovszky P (2013) Resveratrol suppresses PAI-1 gene expression in a human in vitro model of inflamed adipose tissue. Oxid Med Cell Longev 2013:793525CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Zervos IA, Nikolaidis E, Lavrentiadou SN, Tsantarliotou MP, Eleftheriadou EK, Papapanagiotou EP, Fletouris DJ, Georgiadis M, Taitzoglou IA (2011) Endosulfan-induced lipid peroxidation in rat brain and its effect on t-PA and PAI-1: ameliorating effect of vitamins C and E. J Toxicol Sci 36:423–433CrossRefPubMedGoogle Scholar
  64. 64.
    Yamada K, Mizuno M, Nabeshima T (2000) Role for brain-derived neurotrophic factor in learning and memory. Life Sci 70:735–744CrossRefGoogle Scholar
  65. 65.
    Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8:1069–1077CrossRefPubMedGoogle Scholar
  66. 66.
    Bekinschtein P, Cammarota M, Izquierdo I, Medina JH (2007) BDNF and memory formation and storage. Neuroscientist 14:147–156CrossRefPubMedGoogle Scholar
  67. 67.
    Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci USA 105:2711–2716CrossRefPubMedCentralPubMedGoogle Scholar
  68. 68.
    Lu Y, Christian K, Lu B (2008) BDNF: A key regulator for protein synthesis-dependent LTP and longterm memory? Neurobiol Learn Mem 89:312–323CrossRefPubMedCentralPubMedGoogle Scholar
  69. 69.
    Chao MV, Bothwell M (2002) Neurotrophins: to cleave or not to cleave. Neuron 33:9–12CrossRefPubMedGoogle Scholar
  70. 70.
    Ibanez CF (2002) Jekyll-Hyde neurotrophins: the story of proNGF. Trends Neurosci 25:284–286CrossRefPubMedGoogle Scholar
  71. 71.
    Bibel M, Barde YA (2000) Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 14:2919–2937CrossRefPubMedGoogle Scholar
  72. 72.
    Dechant G, Barde YA (2002) The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci 5:1131–1136CrossRefPubMedGoogle Scholar
  73. 73.
    Schinder AF, Poo M (2000) The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci 23:639–645CrossRefPubMedGoogle Scholar
  74. 74.
    Carlino D, Leone E, Di Cola F, Baj G, Marin R, Dinelli G, Tongiorgi E, De Vanna M (2011) Low serum truncated-BDNF isoform correlates with higher cognitive impairment in schizophrenia. J Psychiatr Res 45:273–279CrossRefPubMedGoogle Scholar
  75. 75.
    Barnes P, Thomas KL (2008) Proteolysis of proBDNF is a key regulator in the formation of memory. PLoS One 3:e3248CrossRefPubMedCentralPubMedGoogle Scholar
  76. 76.
    Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276:12660–12666CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Giselli Scaini
    • 1
    • 2
  • Meline O. S. Morais
    • 1
    • 2
  • Camila B. Furlanetto
    • 1
    • 2
  • Luiza W. Kist
    • 2
    • 3
  • Talita C. B. Pereira
    • 2
    • 3
  • Patrícia F. Schuck
    • 4
  • Gustavo C. Ferreira
    • 4
  • Matheus A. B. Pasquali
    • 5
  • Daniel P. Gelain
    • 5
  • José Cláudio F. Moreira
    • 5
  • Maurício R. Bogo
    • 2
    • 3
  • Emilio L. Streck
    • 1
    • 2
    Email author
  1. 1.Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  2. 2.Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM)Porto AlegreBrazil
  3. 3.Laboratório de Biologia Genômica e Molecular, Departamento de Biologia Celular e Molecular, Faculdade de BiociênciasPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  4. 4.Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  5. 5.Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBSUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations