Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

  • Giselli Scaini
  • Gabriela C. Jeremias
  • Camila B. Furlanetto
  • Diogo Dominguini
  • Clarissa M. Comim
  • João Quevedo
  • Patrícia F. Schuck
  • Gustavo C. Ferreira
  • Emilio L. Streck
Research Report
Part of the JIMD Reports book series (JIMD, volume 13)


Maple syrup urine disease (MSUD) is an inborn metabolism error caused by a deficiency of branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to an accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their corresponding α-keto and α-hydroxy acids. Previous reports suggest that MSUD patients are at high risk for chronic neuropsychiatric problems. Therefore, in this study, we assessed variables that suggest depressive-like symptoms (anhedonia as measured by sucrose intake, immobility during the forced swimming test and body and adrenal gland weight) in rats submitted to chronic administration of BCAA during development. Furthermore, we determined if these parameters were sensitive to imipramine and N-acetylcysteine/deferoxamine (NAC/DFX). Our results demonstrated that animals subjected to chronic administration of branched-chain amino acids showed a decrease in sucrose intake without significant changes in body weight. We also observed an increase in adrenal gland weight and immobility time during the forced swimming test. However, treatment with imipramine and NAC/DFX reversed these changes in the behavioral tasks. In conclusion, this study demonstrates a link between MSUD and depression in rats. Moreover, this investigation reveals that the antidepressant action of NAC/DFX and imipramine might be associated with their capability to maintain pro-/anti-oxidative homeostasis.


  1. Araújo P, Wassermann GF, Tallini K et al (2001) Reduction of large neutral amino acid levels in plasma and brain of hyperleucinemic rats. Neurochem Int 38:529–537PubMedCrossRefGoogle Scholar
  2. Arent CO, Réus GZ, Abelaira HM et al (2012) Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats. Neurochem Int 61:1072–80PubMedCrossRefGoogle Scholar
  3. Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW (2002) The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 22:9134–9141PubMedGoogle Scholar
  4. Banjac A, Perisic T, Sato H et al (2008) The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene 27:1618–1628PubMedCrossRefGoogle Scholar
  5. Barschak AG, Sitta A, Deon M et al (2006) Evidence that oxidative stress in increased in plasma from pacients with maple syrup urine disease. Metab Brain Dis 21:279–286PubMedCrossRefGoogle Scholar
  6. Berk M, Malhi GS, Gray LJ, Dean OM (2013) The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 34:167–177PubMedCrossRefGoogle Scholar
  7. 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 21:327–332PubMedCrossRefGoogle Scholar
  8. Bridi R, Fontella FU, Pulrolnik V et al (2006) A chemically-induced acute model of maple syrup urine disease in rats for neurochemical studies. J Neurosci Methods 155:224–230PubMedCrossRefGoogle Scholar
  9. Bridi R, Latini A, Braum CA et al (2005) Evaluation of the mechanisms involved in leucine induced oxidative damage in cerebral cortex of young rats. Free Radic Res 39:71–79PubMedCrossRefGoogle Scholar
  10. Cavalleri F, Berardi A, Burlina AB, Ferrari F, Mavilla L (2002) Diffusion-weighted MRI of maple syrup urine disease encephalopathy. Neuroradiology 44:499–502PubMedCrossRefGoogle Scholar
  11. Chuang DT, Shih VE (2001) Maple syrup urine disease (branchedchain 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
  12. 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
  13. DellaGioia N, Hannestad J (2010) A critical review of human endotoxin administration as an experimental paradigm of depression. Neurosci Biobehav Rev 34:130–143PubMedCentralPubMedCrossRefGoogle Scholar
  14. Dimopoulos N, Piperi C, Psarra V, Lea RW, Kalofoutis A (2008) Increased plasma levels of 8-iso-PGF2alpha and IL-6 in an elderly population with depression. Psychiatry Res 161:59–66PubMedCrossRefGoogle Scholar
  15. Di-Pietro PB, Dias ML, Scaini G et al (2008) Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration. Neurosci Lett 434:139–143PubMedCrossRefGoogle Scholar
  16. Dodd PR, Williams SH, Gundlach AL et al (1992) Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. J Neurochem 59:582–590PubMedCrossRefGoogle Scholar
  17. Ferreira FR, Biojone C, Joca SRL, Guimarães FS (2008) Antidepressant-like effects of N-acetyl-L-cysteine in rats. Behav Pharmacol 19:747–50PubMedCrossRefGoogle Scholar
  18. 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 17:47–54PubMedCrossRefGoogle Scholar
  19. Forlenza MJ, Miller GE (2006) Increased serum levels of 8-hydroxy-2’-deoxyguanosine in clinical depression. Psychosom Med 68:1–7PubMedCrossRefGoogle Scholar
  20. Gamaro GD, Manoli LP, Torres IL, Silveira R, Dalmaz C (2003) Effects of chronic variate stress on feeding behavior and on monoamine levels in different rat brain structures. Neurochem Int 42:107–114PubMedCrossRefGoogle Scholar
  21. Gardner A, Boles RG (2011) Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog Neuro Psychopharmacol Biol Psychiatry 35:730–743CrossRefGoogle Scholar
  22. Gere-Paszti E, Jakus J (2009) The effect of N-acetylcysteine on amphetamine-mediated dopamine release in rat brain striatal slices by ion-pair reversed-phase high performance liquid chromatography. Biomed Chromatogr 23:658–664PubMedCrossRefGoogle Scholar
  23. Gilbert KR, Aizenman E, Reynolds IJ (1991) Oxidized glutathione modulates N-methyl-D-aspartate- and depolarization-induced increases in intracellularCa2+ in cultured rat forebrain neurons. Neurosci Lett 133:11–14PubMedCrossRefGoogle Scholar
  24. Ha JS, Kim TK, Eun BL et al (2004) Maple syrup urine disease encephalopathy: a follow-up study in the acute stage using diffusion-weighted MRI. Pediatr Radiol 34:163–166PubMedCrossRefGoogle Scholar
  25. Howell RK, Lee M (1963) Influence of a-keto acids on the respiration of brain in vitro. Proc Soc Exp Biol Med 113:660–663PubMedCrossRefGoogle Scholar
  26. Hutson SM, Lieth E, LaNoue KF (2001) Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 131:846S–850SPubMedGoogle Scholar
  27. Iyer SS, Jones DP, Brigham KL, Rojas M (2009) Oxidation of plasma cysteine/cystine redox state in endotoxin-induced lung injury. Am J Respir Cell Mol Biol 40:90–98PubMedCentralPubMedCrossRefGoogle Scholar
  28. Janáky R, Dohovics R, Saransaari P, Oja SS (2007) Modulation of [3H]dopamine release by glutathione in mouse striatal slices. Neurochem Res 32:1357–1364PubMedCrossRefGoogle Scholar
  29. Jou SH, Chiu NY, Liu CS (2009) Mitochondrial dysfunction and psychiatric disorders. Chang Gung Med J 32:370–379PubMedGoogle Scholar
  30. 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 11:1919–1932PubMedCentralPubMedCrossRefGoogle Scholar
  31. Katz RJ, Roth KA, Carroll BJ (1981a) Acute and chronic stress effects on open field activity in the rat: implications for a model of depression. Neurosci Biobehav Rev 5:247–251PubMedCrossRefGoogle Scholar
  32. Katz RJ, Roth KA, Carroll BJ (1981b) Animal models and human depressive disorders. Neurosci Biobehav Rev 5:231–246PubMedCrossRefGoogle Scholar
  33. Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R (2003) Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Rep 8:365–370PubMedCrossRefGoogle Scholar
  34. Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902PubMedCentralPubMedCrossRefGoogle Scholar
  35. Kumar A, Garg R (2009) Possible role of trazodone and imipramine in sleep deprivation-induced anxiety-like behavior and oxidative damage in mice. Methods Find Exp Clin Pharmacol 31:383–387PubMedGoogle Scholar
  36. Lafleur DL, Pittenger C, Kelmendi B et al (2006) N-Acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive– compulsive disorder. Psychopharmacology 184:254–256PubMedCrossRefGoogle Scholar
  37. 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 26:823–830PubMedCrossRefGoogle Scholar
  38. Leslie SW, Brown LM, Trent RD et al (1992) Stimulation of N-methyl-D-aspartate receptor-mediated calcium entry into dissociated neurons by reduced and oxidized glutathione. Mol Pharmacol 41:308–314PubMedGoogle Scholar
  39. Linck VM, Costa-Campos L, Pilz LK, Garcia CRL, Elisabetsky E (2012) AMPA glutamate receptors mediate the antidepressant-like effects of N-acetylcysteine in the mouse tail suspension test. Behav Pharmacol 23:171–177PubMedCrossRefGoogle Scholar
  40. Lucca G, Comim CM, Valvassori SS et al (2008) Chronic mild stress paradigm reduces sweet food intake in rats without affecting brain derived neurotrophic factor protein levels. Curr Neurovasc Res 5:207–213PubMedCrossRefGoogle Scholar
  41. Maes M, De Vos N, Pioli R et al (2000) Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defences in that illness J Affect Disord 58(3):241–246Google Scholar
  42. Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro) degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 35:676–92PubMedCrossRefGoogle Scholar
  43. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009a) Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett 30:715–722PubMedGoogle Scholar
  44. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009b) Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocinol Lett 30:462–469Google Scholar
  45. Magalhães PV, Dean OM, Bush AI et al (2011) N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial. J Affect Disord 129:317–20PubMedCrossRefGoogle Scholar
  46. Mescka C, Moraes T, Rosa A et al (2011) In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease. Metab Brain Dis 26:21–28PubMedCrossRefGoogle Scholar
  47. Mokoena ML, Harvey BH, Oliver DW, Brink CB (2010) Ozone modulates the effects of imipramine on immobility in the forced swim test, and nonspecific parameters of hippocampal oxidative stress in the rat. Metab Brain Dis 25:125–133PubMedCrossRefGoogle Scholar
  48. Muelly ER, Moore GJ, Bunce SC et al (2013) Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J Clin Invest 123(4):1809–20PubMedCentralPubMedCrossRefGoogle Scholar
  49. Nestler EJ, Gould E, Manji H et al (2002) Preclinical model: status of basic research in depression. Biol Psychiatry 52:503–528PubMedCrossRefGoogle Scholar
  50. 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 28:675–679PubMedCrossRefGoogle Scholar
  51. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 21:266–730Google Scholar
  52. Prensky AL, Moser HW (1966) Brain lipids, proteolipids, and free amino acids in maple syrup urine disease. J Neurochem 13:863–874PubMedCrossRefGoogle Scholar
  53. 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 14:117–121PubMedCrossRefGoogle Scholar
  54. Réus GZ, Stringari RB, de Souza B et al (2010) Harmine and imipramine promote antioxidant activities in prefrontal cortex and hippocampus. Oxid Med Cell Longev 3:325–331PubMedCentralPubMedCrossRefGoogle Scholar
  55. Réus GZ, Stringari RB, Ribeiro KF et al (2011) Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res 221:166–171PubMedCrossRefGoogle Scholar
  56. Ribeiro CA, Sgaravatti AM, Rosa RB et al (2008) Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res 33:114–124PubMedCrossRefGoogle Scholar
  57. Scaini G, de Rochi N, Jeremias IC et al (2012) Evaluation of acetylcholinesterase in an animal model of maple syrup urine disease. Mol Neurobiol 45:279–86PubMedCrossRefGoogle Scholar
  58. Scaini G, Comim CM, Oliveira GM et al (2013a) Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model. J Inherit Metab Dis 36:721–730PubMedCrossRefGoogle Scholar
  59. Scaini G, Mello-Santos LM, Furlanetto CB et al (2013b) Acute and chronic administration of the branched-chain amino acids decreases nerve growth factor in rat hippocampus. Mol Neurobiol. doi:10.1007/s12035-013-8447-1 Google Scholar
  60. 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 82:69–75PubMedCrossRefGoogle Scholar
  61. Sgaravatti AM, Rosa RB, Schuck PF et al (2003) Inhibition of brain energy metabolism by the a-keto acids accumulating in maple syrup urine disease. Biochim Biophys Acta 1639:232–238PubMedCrossRefGoogle Scholar
  62. Smaga I, Pomierny B, Krzyżanowska W et al (2012) N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats. Prog Neuropsychopharmacol Biol Psychiatry 39:280–87PubMedCrossRefGoogle Scholar
  63. Strauss KA, Puffenberger EG, Morton DH (2006) Maple syrup urine disease. In: Pagon R, Bird T, Dolan C, Stephens K, Adam M (eds) GeneReviews. University of Washington, Seattle, Washington, USAGoogle Scholar
  64. Taketomi T, Kunishita T, Hara A, Mizushima S (1983) Abnormal protein and lipid compositions of the cerebral myelin of a patient with maple syrup urine disease. Jpn J Exp Med 53:109–116PubMedGoogle Scholar
  65. 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 181:44–49PubMedCrossRefGoogle Scholar
  66. 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 15:121–135PubMedCrossRefGoogle Scholar
  67. Tribble D, Shapira R (1983) Myelin proteins: degradation in rat brain initiated by metabolites causative of maple syrup urine disease. Biochem Biophys Res Commun 114:440–446PubMedCrossRefGoogle Scholar
  68. Tuon L, Comim CM, Antunes MM et al (2007) Imipramine reverses the depressive symptoms in sepsis survivor rats. Intensive Care Med 33:2165–2167PubMedCrossRefGoogle Scholar
  69. Varga V, Jenei Z, Janáky R, Saransaari P, Oja SS (1997) Glutathione is an endogenous ligand of rat brain N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Neurochem Res 22:1165–1171PubMedCrossRefGoogle Scholar
  70. Venè R, Castellani P, Delfino L, Lucibello M, Ciriolo MR, Rubartelli A (2011) The cystine/cysteine cycle and GSH are independent and crucial antioxidant systems in malignant melanoma cells and represent druggable targets. Antioxid Redox Signal 15:2439–2453PubMedCrossRefGoogle Scholar
  71. Wajner M, Coelho DM, Barschak AG et al (2000) Reduction of large neutral amino acid concentration in plasma and CSF of patients with maple syrup urine disease during crises. J Inherit Metab Dis 23:505–512PubMedCrossRefGoogle Scholar
  72. Wajner M, Vargas CR (1999) Reduction of plasma concentrations of large neutral amino acids in patients with maple urine disease during crises. Arch Dis Child 80:579PubMedCentralPubMedCrossRefGoogle Scholar
  73. Walterfang M, Bonnot O, Mocellin R, Velakoulis D (2013) The neuropsychiatry of inborn errors of metabolism. J Inherit Metab Dis 36(4):687–702PubMedCrossRefGoogle Scholar
  74. Willner P, Benton D, Brown E et al (1998) “Depression” increases “craving” for sweet rewards in animal and human models of depression and craving. Psychopharmacology 136:272–283PubMedCrossRefGoogle Scholar
  75. Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 93:358–364PubMedCrossRefGoogle Scholar
  76. Yagasaki Y, Numakawa T, Kumamaru E, Hayashi T, Su TP, Kunugi H (2006) Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem 281:12941–12949PubMedCrossRefGoogle Scholar
  77. Yudkoff M, Daikhin Y, Lin ZP et al (1994) Interrelationships of leucine and glutamate metabolism in cultured astrocyts. J Neurochem 62:1192–1202PubMedCrossRefGoogle Scholar
  78. 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 40:347–54PubMedCrossRefGoogle Scholar
  79. Zinnanti WJ, Lazovic J, Griffin K et al (2009) Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain 132:903–918PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Giselli Scaini
    • 1
    • 2
  • Gabriela C. Jeremias
    • 1
    • 2
  • Camila B. Furlanetto
    • 1
    • 2
  • Diogo Dominguini
    • 2
    • 3
  • Clarissa M. Comim
    • 2
    • 3
  • João Quevedo
    • 2
    • 3
  • Patrícia F. Schuck
    • 4
  • Gustavo C. Ferreira
    • 4
  • Emilio L. Streck
    • 1
    • 2
  1. 1.Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul Catarinense CriciúmaCriciúmaBrazil
  2. 2.Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM)Porto AlegreBrazil
  3. 3.Laboratório de Neurociências, Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  4. 4.Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil

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