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An Evaluation of the Effects of Acute and Chronic l-Tyrosine Administration on BDNF Levels and bdnf mRNA Expression in the Rat Brain

Molecular Neurobiology volume 49, pages 734–740 (2014)Cite this article

Abstract

Tyrosinemia type II, which is also known as Richner–Hanhart syndrome, is an inborn error of metabolism that is due to a block in the transamination reaction that converts tyrosine to p-hydroxyphenylpyruvate. Because the mechanisms of neurological dysfunction in hypertyrosinemic patients are poorly known and the symptoms of these patients are related to the central nervous system, the present study evaluated brain-derived neurotrophic factor (BDNF) levels and bdnf mRNA expression in young rats and during growth. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal l-tyrosine injection (500 mg/kg) or saline. Chronic administration consisted of l-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old), and the rats were killed 12 h after the last injection. The brains were rapidly removed, and we evaluated the BDNF levels and bdnf mRNA expression. The present results showed that the acute administration of l-tyrosine decreased both BDNF and bdnf mRNA levels in the striatum of 10-day-old rats. In the 30-day-old rats, we observed decreased BDNF levels without modifications in bdnf transcript level in the hippocampus and striatum. Chronic administration of l-tyrosine increased the BDNF levels in the striatum of rats during their growth, whereas bdnf mRNA expression was not altered. We hypothesize that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. The present results enhance our knowledge of the pathophysiology of hypertyrosinemia.

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References

  1. Held PK (2006) Disorders of tyrosine catabolism. Mol Genet Metab 88:103–106

    CAS  PubMed  Article  Google Scholar 

  2. Mitchell GA, Grompe M, Lambert M, Tanguay RM (2001) Hypertyrosinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle U (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 1977–1982

    Google Scholar 

  3. Scott CR (2006) The genetic tyrosinemias. Am J Med Genet C: Semin Med Genet 142:121–126

    Article  Google Scholar 

  4. Buist NRM, Kennaway NG, Fellmann JH (1985) Tyrosinaemia type II. In: Inherited diseases of amino acid metabolism (Bickel H, Wachtel U, eds) Thieme Stuttgart pp 203–235

  5. Goldsmith LA, Laberge C (1989) Tyrosinemia and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle U (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 547–562

    Google Scholar 

  6. Sener RN (2005) Brain magnetic resonance imaging in tyrosinemia. Acta Radiol 46:618–620

    CAS  PubMed  Article  Google Scholar 

  7. Goldsmith LA, Kang E, Bienfang DC, Jimbow K, Gerald P, Baden HP (1973) Tyrosinemia with plantar and palmar keratosis and keratitis. J Pediatr 83:798–805

    CAS  PubMed  Article  Google Scholar 

  8. Lemonnier F, Charpentier C, Odievre M, Larregue M, Lemonnier A (1979) Tyrosine aminotransferase isoenzyme deficiency. J Pediatr 94:931–932

    CAS  PubMed  Article  Google Scholar 

  9. Rabinowitz LG, Williams LR, Anderson CE, Mazur A, Kaplan P (1995) Painful keratoderma and photophobia: hallmarks of tyrosinemia type II. J Pediatr 126:266–269

    CAS  PubMed  Article  Google Scholar 

  10. Macsai MS, Schwartz TL, Hinkle D, Hummel MB, Mulhern MG, Rootman D (2001) Tyrosinemia type II: nine cases of ocular signs and symptoms. Am J Ophthalmol 132:522–527

    CAS  PubMed  Article  Google Scholar 

  11. Valikhani M, Akhyani M, Jafari AK, Barzegari M, Toosi S (2005) Oculocutaneous tyrosinaemia or tyrosinaemia type 2: a case report. J Eur Acad Dermatol Venereol 20:591–594

    Article  Google Scholar 

  12. Lewin GR, Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289–317

    CAS  PubMed  Article  Google Scholar 

  13. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat Rev Neurosci 4:299–309

    CAS  PubMed  Article  Google Scholar 

  14. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642

    CAS  PubMed  Article  Google Scholar 

  15. 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 276:12660–12666

    CAS  PubMed  Article  Google Scholar 

  16. Chao MV, Bothwell M (2002) Neurotrophins: to cleave or not to cleave. Neuron 33:9–12

    CAS  PubMed  Article  Google Scholar 

  17. Lu Y, Christian K, Lu B (2008) BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 89:312–323

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948

    CAS  PubMed  Article  Google Scholar 

  19. 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 8:1069–1077

    CAS  PubMed  Article  Google Scholar 

  20. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92:8856–8860

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. 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 381:706–709

    CAS  PubMed  Article  Google Scholar 

  22. 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 16:1137–1145

    CAS  PubMed  Article  Google Scholar 

  23. Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32

    CAS  PubMed  Article  Google Scholar 

  24. Soule J, Messaoudi E, Bramham CR (2006) Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. Biochem Soc Trans 34:600–604

    CAS  PubMed  Article  Google Scholar 

  25. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2006) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224–237

    Article  Google Scholar 

  26. Bekinschtein P, Cammarota M, Izquierdo I, Medina JH (2007) BDNF and memory formation and storage. Neuroscientist 14:47–156

    Article  Google Scholar 

  27. Gwag BJ, Koh JY, Chen MM, Dugan LL, Behrens MM, Lobner D, Choi DW (1995) BDNF or IGF-I potentiates free radical-mediated injury in cortical cell cultures. Neuroreport 7:93–96

    CAS  PubMed  Article  Google Scholar 

  28. Koh JY, Gwag BJ, Lobner D, Choi DW (1995) Potentiated necrosis of cultured cortical neurons by neurotrophins. Science 268:573–575

    CAS  PubMed  Article  Google Scholar 

  29. Cunha C, Angelucci A, D'Antoni A, Dobrossy MD, Dunnett SB, Berardi N, Brambilla R (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol Dis 33:358–368

    CAS  PubMed  Article  Google Scholar 

  30. Bongiovanni R, Yamamoto BK, Simpson C, Jaskiw GE (2003) Pharmacokinetics of systemically administered tyrosine: a comparison of serum, brain tissue and in vivo microdialysate levels in the rat. J Neurochem 87:310–317

    CAS  PubMed  Article  Google Scholar 

  31. Morre MC, Hefti F, Wurtman RJ (1980) Regional tyrosine levels in rat brain after tyrosine administration. J Neural Transm 49:45–50

    CAS  PubMed  Article  Google Scholar 

  32. Lowry HO, Rosebough NG, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  33. Bonefeld BE, Elfving B, Wegener G (2008) Reference genes for normalization: a study of rat brain tissue. Synapse 62:302–309

    CAS  PubMed  Article  Google Scholar 

  34. Livak KJ, Schmittgen TD (2008) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408

    Article  Google Scholar 

  35. Baydyuk M, Russell T, Liao GY, Zang K, An JJ, Reichardt LF, Xu B (2011) TrkB receptor controls striatal formation by regulating the number of newborn striatal neurons. Proc Natl Acad Sci U S A 108:1669–1674

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. Gokce O, Runne H, Kuhn A, Luthi-Carter R (2009) Short-term striatal gene expression responses to brain-derived neurotrophic factor are dependent on MEK and ERK activation. PLoS One 4:e5292

    PubMed Central  PubMed  Article  Google Scholar 

  37. Jana S, Sinha M, Chanda D, Roy T, Banerjee K, Munshi S, Patro BS, Chakrabarti S (2011) Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease. Biochim Biophys Acta 1812:663–673

    CAS  PubMed  Article  Google Scholar 

  38. Boyd JG, Gordon T (2002) A dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor. Eur J Neurosci 15:613–626

    CAS  PubMed  Article  Google Scholar 

  39. Croll SD, Suri CD, Compton L, Simmons MV, Yancopoulos GD, Lindsay RM, Wiegand SJ, Rudge JS, Scharfman HE (1999) Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex. Neuroscience 93:1491–1506

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25:5455–5463

    CAS  PubMed  Article  Google Scholar 

  41. Wu K, Xu JL, Suen PC, Levine E, Huang YY, Mount HT, Lin SY, Black IB (1996) Functional TrkB neurotrophin receptors are intrinsic components of the adult brain postsynaptic density. Mol Brain Res 43:286–290

    CAS  PubMed  Article  Google Scholar 

  42. Kapczinski F, Frey BN, Andreazza AC, Kauer-Sant'Anna M, Cunha AB, Post RM (2008) Increased oxidative stress as a mechanism for decreased BDNF levels in acute manic episodes. Rev Bras Psiquiatr 30:243–245

    PubMed  Article  Google Scholar 

  43. Zou J, Crews F (2006) CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death. Cell Mol Neurobiol 26:385–405

    CAS  PubMed  Article  Google Scholar 

  44. Pugazhenthi S, Phansalkar K, Audesirk G, West A, Cabell L (2006) Differential regulation of c-jun and CREB by acrolein and 4-hydroxynonenal. Free Radic Biol Med 40:21–34

    CAS  PubMed  Article  Google Scholar 

  45. Sgaravatti AM, Magnusson AS, de Oliveira AS, Rosa AP, Mescka CP, Zanin FR, Pederzolli CD, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS (2009) Tyrosine administration decreases glutathione and stimulates lipid and protein oxidation in rat cerebral cortex. Metab Brain Dis 24:415–425

    CAS  PubMed  Article  Google Scholar 

  46. Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, Meuth S, Nagy A, Greene RW, Nestler EJ (2004) Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A 101:10827–10832

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  47. Morgane PJ, Austin-LaFrance RJ, Bronzino JD, Tonkiss J, Galler JR (1992) Malnutrition and the developing central nervous system. In: Isaacson RL, Jensen KF (eds) The vulnerable brain: nutrition and toxins. Plenum, New York, pp 3–44

    Chapter  Google Scholar 

  48. Slotkin TA, Oliver CA, Seidler FJ (2005) Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. Brain Res Dev Brain Res 157:172–180

    CAS  PubMed  Article  Google Scholar 

  49. Uylings HB (2000) Development of the cerebral cortex in rodents and man. Eur J Morphol 38:309–312

    CAS  PubMed  Article  Google Scholar 

  50. Matté C, Mackedanz V, Stefanello FM, Scherer EBS, Andreazza AC, Zanotto C, Moro AM, Garcia SC, Gonçalves CAS, Erdtmann B, Salvador M, Wyse ATS (2009) Chronic hyperhomocysteinemia alters antioxidant defenses and increases DNA damage in brain and blood of rats: protective effect of folic acid. Neurochem Int 54:7–13

    PubMed  Article  Google Scholar 

  51. Kim EY, Hong YB, Go SH, Lee B, Jung SC (2006) Downregulation of neurotrophic factors in the brain of a mouse model of Gaucher disease; implications for neuronal loss in Gaucher disease. Exp Mol Med 38:348–356

    CAS  PubMed  Article  Google Scholar 

  52. Zhang Y, Zhao J, Wang J, Jio X (2010) Brain-derived neurotrophic factor inhibits phenylalanine-induced neuronal apoptosis by preventing RhoA pathway activation. Neurochem Res 35:480–486

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

This research was supported by grants from Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Affiliations

  1. Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, 88806-000, Santa Catarina, Brazil

    Gabriela K. Ferreira, Giselli Scaini, Isabela C. Jeremias, Milena Carvalho-Silva, Cinara L. Gonçalves & Emilio L. Streck

  2. Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, Rio Grande do Sul, Brazil

    Gabriela K. Ferreira, Giselli Scaini, Isabela C. Jeremias, Milena Carvalho-Silva, Cinara L. Gonçalves, Talita C. B. Pereira, Giovanna M. T. Oliveira, Luiza W. Kist, Maurício R. Bogo & Emilio L. Streck

  3. Center of Excellence in Applied Neuroscience of Santa Catarina (NENASC), Florianópolis, Brazil

    Gabriela K. Ferreira, Giselli Scaini, Isabela C. Jeremias, Milena Carvalho-Silva, Cinara L. Gonçalves & Emilio L. Streck

  4. Laboratório de Biologia Genômica e Molecular, Departamento de Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil

    Talita C. B. Pereira, Giovanna M. T. Oliveira, Luiza W. Kist & Maurício R. Bogo

  5. Laboratório de Erros Inatos do Metabolismo, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, Santa Catarina, Brazil

    Patrícia F. Schuck & Gustavo C. Ferreira

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  1. Gabriela K. Ferreira
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  2. Giselli Scaini
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  7. Giovanna M. T. Oliveira
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Correspondence to Emilio L. Streck.

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Highlights

- Effects of administration of l-tyrosine on protein levels and mRNA expression of BDNF

- Acute administration decreased BDNF and bdnf mRNA levels in the striatum of 10-day-old rats

- Acute administration decreased BDNF levels in the hippocampus and striatum of 30-day-old rats

- Chronic administration of l-tyrosine increased BDNF levels in the striatum of rats

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Ferreira, G.K., Scaini, G., Jeremias, I.C. et al. An Evaluation of the Effects of Acute and Chronic l-Tyrosine Administration on BDNF Levels and bdnf mRNA Expression in the Rat Brain. Mol Neurobiol 49, 734–740 (2014). https://doi.org/10.1007/s12035-013-8552-1

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Keywords

  • l-tyrosine
  • Tyrosinemia type II
  • Richner–Hanhart syndrome
  • Brain-derived neurotrophic factor
  • Brain