Metabolic Brain Disease

, Volume 31, Issue 2, pp 363–368 | Cite as

Chemically induced acute model of sarcosinemia in wistar rats

  • Rodrigo Binkowski de Andrade
  • Tanise Gemelli
  • Denise Bertin Rojas
  • Carlos Severo Dutra-Filho
  • Clovis Milton Duval Wannmacher
Original Article


In the present study, we developed an acute chemically induced model of sarcosinemia in Wistar rats. Wistar rats of 7, 14 and 21 postpartum days received sarcosine intraperitoneally in doses of 0.5 mmol/Kg of body weight three time a day at intervals of 3 h. Control animals received saline solution (NaCl 0.85 g%) in the same volume (10 mL/Kg of body weight). The animals were killed after 30 min, 1, 2, 3 or 6 h after the last injection and the brain and the blood were collected for sarcosine measurement. The results showed that plasma and brain sarcosine concentrations achieved levels three to four times higher than the normal levels and decreased in a time-dependent way, achieving normal levels after 6 hours. Considering that experimental animal models are useful to investigate the pathophysiology of human disorders, our model of sarcosinemia may be useful for the research of the mechanisms of neurological dysfunction caused by high tissue sarcosine levels.


Sarcosinemia Metabolic disease Animal model Sarcosine 



This work was supported by the research grants from Programa de Núcleos de Excelência (PRONEX), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and FINEP Rede Instituto Brasileiro de Neurociência.


  1. Bar-Joseph I, Pras E, Reznik-Wolf H, et al. (2012) Mutations in the sarcosine dehydrogenase gene in patients with sarcosinemia. Hum Genet 131:1805–1810CrossRefPubMedGoogle Scholar
  2. Bayer SA, Altman J (1995) Principles of neurogenesis, neuronal migration, and neural circuit formation. In: Paxinos G (ed) The rat nervous system, 3rd edn. Academic Press, San Diego, pp. 1079–1098Google Scholar
  3. Bayer SA, Altman J, Russo RJ, Zhang X (1993) Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology 14:83–144PubMedGoogle Scholar
  4. Bergeron F, Otto A, Blache P, Day R, Denoroy L, Brandsch R, Bataille D (1998) Molecular cloning and tissue distribution of rat sarcosine dehydrogenase. Eur J Biochem 257:556–561CrossRefPubMedGoogle Scholar
  5. 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 Meth 155:224–230CrossRefGoogle Scholar
  6. Brusque AM, Mello CF, Buchanan DN, Terraciano ST, Rocha MP, Vargas CR (1999) Effect of chemically induced propionic acidemia on neurobehavioural development of rats. Pharmacol Biochem Behav 64:529–534CrossRefPubMedGoogle Scholar
  7. Cicero TJ, Adams ML, Giordano A, Miller BT, O’Connor L, Nock B (1990) Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring. J Pharmacol Exp Ther 256:1086–1093Google Scholar
  8. Clark JB, Bates TE, Cullingford T, Land JM (1993) Development of enzymes of energy metabolism in the neonatal mammalian brain. Dev Neurosci 15:174–180CrossRefPubMedGoogle Scholar
  9. Deutsch SI, Rosse RB, Long KD, Gaskins B, Mastropaolo J (2006) Rare neurodevelopmental abnormalities of sarcosinemia may involve glycinergic stimulation of a primed N-methyl-d-aspartate receptor. Clin Neuropharmacol 29:361–363CrossRefPubMedGoogle Scholar
  10. Dutra JC, Wajner M, Wannmacher CMD, Wannmacher LE, Pires RF, Rosa-Junior A (1991) Effect of postnatal methylmalonate administration on adult rat behavior. Braz J Med Biol Res 24:595–605PubMedGoogle Scholar
  11. Enesco M, Leblond CP (1962) Increase in cell number as a factor in the growth of the organs and tissues of the young male rat. J Embryol Exp Morphol 10:530–562Google Scholar
  12. Gemelli T, de Andrade RB, Rojas DB, Bonorino NF, Mazzola PN, Tortorelli LS, Funchal C, Dutra-Filho CS, Wannmacher CMD (2013) Effects of b-alanine administration on selected parameters of oxidative stress and phosphoryltransfer network in cerebral cortex and cerebellum of rats. Mol Cell Biochem 80:161–170. doi: 10.1007/s11010-013-1669-8 CrossRefGoogle Scholar
  13. Gerritsen T, Waisman HA (1966) Hypersarcosinemia: an inborn error of metabolism. N Engl J Med 275:66–69CrossRefPubMedGoogle Scholar
  14. Harding CO, Williams P, Pflanzer DM, Colwell RE, Lyne PW, Wolff JA (1992) SAR: a genetic mouse model for human sarcosinemia generated by ethylnitrosourea mutagenesis. Proc Nat Acad Sci. 89: 2644–2648Google Scholar
  15. Herdon HJ, Godfrey FM, Brown AM, Coulton S, Evans JR, Cairns WJ (2001) Pharmacological assessment of the role of the glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes. Neuropharmacology 41:88–96CrossRefPubMedGoogle Scholar
  16. Himwich WA (1973) Problems in interpreting neurochemical changes occurring in developing and aging animals. In: Ford DH (ed) Neurobiological effects of maturation and aging. Progress in Brain Research, Elsevier Scientific, Amsterdam, pp. 13–23CrossRefGoogle Scholar
  17. Jacobson M (1978) Histogenesis and morphogenesis of the central nervous system. In: Jacobson M (ed) Developmental neurobiology. Plenum Press, New York, pp. 57–114CrossRefGoogle Scholar
  18. Jiang Y, Cheng X, Wang C, Ma Y (2010) Quantitative determination of sarcosine and related compounds in urinary samples by liquid chromatography with tandem mass spectrometry. Anal Chem 82:9022–9027. doi: 10.1021/ac1019914 CrossRefPubMedGoogle Scholar
  19. Kimmel CA (1998) Current approaches. In: Slikker WJr, Chang LW (ed) Developmental neurotoxicology, Academic Press, San Diego, pp 675–685Google Scholar
  20. Kracht LW, Friese M, Herholz K, Schroeder R, Bauer B, Jacobs A, Heiss WD (2003) Methyl-[11C]- l-methionine uptake as measured by positron emission tomography correlates to microvessel density in patients with glioma. Eur J Nucl Med Mol Imaging 30:868–873CrossRefPubMedGoogle Scholar
  21. Krinke G, Eisenbrandt DL (1994) In: Mohr U, Dungworth DL, Capen CC (eds) Pathobiology of the aging rat. ILSI Press, Washington DC, pp. 3–9Google Scholar
  22. Lopez-Corcuera B, Martinez-Maza R, Nunez E, Roux M, Supplisson S, Aragon C (1998) Differential properties of two stably expressed brain-specific glycine transporters. J Neurochem 71:2211–2219CrossRefPubMedGoogle Scholar
  23. Mallorga PJ, Williams JB, Jacobson M, Marques R, Chaudhary A, Conn PJ, Pettibone DJ, Sur C (2003) Pharmacology and expression analysis of glycine transporter GlyT1 with [3 H]-(N-[3-(4′-fluorophenyl)-3-(4′phenylphenoxy)propyl])sarcosine. Neuropharmacology 45:585–593CrossRefPubMedGoogle Scholar
  24. Marzo A (1997) Clinical pharmacokinetic registration file for NDA and ANDA procedures. Pharmacol Res 36:425–450CrossRefPubMedGoogle Scholar
  25. Moreira JC, Wannmacher CMD, Costa SM, Wajner M (1989) Effect of proline administration on rat behavior in aversive and nonaversive tasks. Pharmacol Biochem Behav 32:885–890CrossRefPubMedGoogle Scholar
  26. O’Kane RL, Hawkins RA (2003) Na + −dependent transport of large neutral amino acids occurs at the abluminal membrane of the blood-brain barrier. Am J Physiol Endocrinol Metab 285:1167–1173CrossRefGoogle Scholar
  27. Ross EM, Gilman AG (1990) Pharmacodynamics: mechanism of drug action and the relationship between drug concentration and effect. In: Gilman AG, Goodman LS, Rall TW, Murad F (eds) The pharmacological basis of therapeutics, 8rd edn. Macmillan Publishing Company, New York chapter 2Google Scholar
  28. Schardein JL (1998) Animal/human concordance in: slikker WJr, Chang LW (ed) handbook of developmental neurotoxicology. Academic Press, San Diego, pp. 687–708CrossRefGoogle Scholar
  29. Schulze C, Firth JA (1992) Interendothelial junctions during blood-brain barrier development in the rat: morphological changes at the level of individual tight junctional contacts. Dev Brain Res 69:85–95CrossRefGoogle Scholar
  30. Scott CR (2001) Sarcosinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. The McGraw-Hill Companies, New York, pp. 2057–2063Google Scholar
  31. Sgaravatti AM, Vargas BA, Zandoná BR, Deckmann KB, Rockenbach FJ, Moraes TB, Monserrat JM, Sgarbi MB, Pederzolli CD, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS (2008) Tyrosine promotes oxidative stress in cerebral cortex of young rats. Int J Dev Neurosci 26:551–559CrossRefPubMedGoogle Scholar
  32. Skvorak KJ (2009) Animal models of maple syrup urine disease. J Inherit Metab Dis 32:229–246CrossRefPubMedGoogle Scholar
  33. Smith KE, Borden LA, Hartig PR, Branchek T, Weinshank RL (1992) Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron 8:927–935CrossRefPubMedGoogle Scholar
  34. Socala K, Nieoczym D, Rundfeldt C, Wlaz (2010) Effects of sarcosine, a glycine transporter type 1 inhibitor, in two mouse seizure models. Pharmacol Rep 62: 392–397Google Scholar
  35. Stefanello FM, Matté C, Scherer EB, Wannmacher CMD, Wajner M, Wyse ATS (2007) Chemically induced model of hypermethioninemia in rats. J Neurosci Methods 160:1–4CrossRefPubMedGoogle Scholar
  36. Streck EL, Matté C, Vieira PS, Rombaldi F, Wannmacher CMD, Wajner M (2002) Reduction of Na+,K + −ATPase activity in hippocampus of rats subjected to chemically induced hyperhomocysteinemia. Neurochem Res 27:1593–1598CrossRefPubMedGoogle Scholar
  37. Ueland PM, Midttun O, Windelberg A, Svardal A, Skalevik R, Hustad S (2007) Quantitative profiling of folate and one-carbon metabolism in large-scale epidemiological studies by mass spectrometry. Clin Chem Lab Med 45:1737–1745CrossRefPubMedGoogle Scholar
  38. Winick M, Noble A (1965) Quantitative changes in DNA, RNA and protein during prenatal and postnatal growth in rat. Dev Biol 12:451–466CrossRefPubMedGoogle Scholar
  39. Wyse ATS, Sarkis JJF, Cunha-Filho JS, Teixeira MV, Schetinger MR, Wajner M (1995) ATP diphosphohydrolase activity in synaptosomes from cerebral cortex of rats subjected to chemically induced phenylketonuria. Braz J Med Biol Res 28:643–649PubMedGoogle Scholar
  40. Wyse ATS, Sarkis JJF, Cunha-Filho JS, Teixeira MV, Schetinger MR, Wajner M, et al. (1994) Effect of phenylalanine and its metabolites on ATP diphosphohydrolase activity in synaptosomes from rat cerebral cortex. Neurochem Res 19:1175–1180CrossRefPubMedGoogle Scholar
  41. Zhang HX, Hyrc K, Thio LL (2009) The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine. J Physiol 587:3207–3220CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Rodrigo Binkowski de Andrade
    • 1
  • Tanise Gemelli
    • 1
  • Denise Bertin Rojas
    • 1
  • Carlos Severo Dutra-Filho
    • 1
  • Clovis Milton Duval Wannmacher
    • 1
    • 2
  1. 1.PPG Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGSPorto AlegreBrazil
  2. 2.Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de BioquímicaPorto AlegreBrazil

Personalised recommendations