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Chronic postnatal ornithine administration to rats provokes learning deficit in the open field task

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Abstract

Hyperornithinemia is the biochemical hallmark of hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2–5 μmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.

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References

  • Amaral AU, Leipnitz G, Fernandes CG, Seminotti B, Zanatta A, Viegas CM, Dutra-Filho CS, Wajner M (2009) Evidence that the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome induce oxidative stress in brain of young rats. Int J Dev Neurosci 27:635–641. doi:10.1016/j.ijdevneu.2009.08.004

    Article  PubMed  CAS  Google Scholar 

  • Andersen AE, Guroff G (1972) Enduring behavioral changes in rats with experimental phenylketonuria. Proc Natl Acad Sci U S A 69(4):863–867

    Article  PubMed  CAS  Google Scholar 

  • Barros DM, Izquierdo LA, Mello e Souza T, Ardenghi PG, Pereira P, Medina JH et al (2000) Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats. Behav Brain Res 114:183–92

    Article  PubMed  CAS  Google Scholar 

  • Bickford PC, Shukitt-Hale B, Joseph J (1999) Effects of aging on cerebellar noradrenergic function and motor learning: nutritional interventions. Mech Ageing Dev 111:141–154

    Article  PubMed  CAS  Google Scholar 

  • Bolles RC (1960) Grooming behavior in the rat. J Comp Physiol Psychol 53:306–310

    Article  PubMed  CAS  Google Scholar 

  • da Silva VA, Malheiros LR, Bueno FMR (1990) Effect of toluene exposure during gestation on neurobehavioral development of rats and hamsters. Braz J Med Biol Res 23:533–537

    Google Scholar 

  • da Silva AL, Piato AL, Bardini S, Netto CA, Nunes DS, Elisabetsky E (2004) Memory retrieval improvement by Ptychopetalum olacoides in young and aging mice. J Ethnopharmacol 95(2–3):199–203. doi:10.1016/j.jep.2004.07.019

    Article  PubMed  Google Scholar 

  • Davis PH, Squire LR (1984) Protein synthesis and memory: a review. Psychol Bull 96:518–559

    Article  PubMed  CAS  Google Scholar 

  • Debray FG, Lambert M, Lemieux B, Soucy JF, Drouin R, Fenyves D, Dubé J, Maranda B, Laframboise R, Mitchell GA (2008) Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. J Med Genet 45(11):759–764. doi:10.1136/jmg.2008.059097

    Article  PubMed  CAS  Google Scholar 

  • Denenberg VH (1969) Open-field bheavior in the rat: what does it mean? Ann N Y Acad Sci 159(3):852–859

    Article  PubMed  CAS  Google Scholar 

  • Devés R, Angelo S, Rojas AM (1998) System yL: the broad scope and cation modulated amino acid transporter. Exp Physiol 83:211–220

    PubMed  Google Scholar 

  • Dreyfus H, Ferret B, Harth S, Giorgio A, Durand M, Freysz L et al (1984) Metabolism and function of gangliosides in developing neurons. J Neurosci Res 12:311–322

    Article  PubMed  CAS  Google Scholar 

  • Dutra JC, Wajner M, Wannmacher CM, Wannmacher LE, Pires RF, Rosa-Junior A (1991) Effect of postnatal methylmalonate administration on adult rat behavior. Braz J Med Biol Res 24(6):595–605

    PubMed  CAS  Google Scholar 

  • Dutra JC, Wajner M, Wannmacher CMD, Dutra-Filho CS, Rache E (1993) Inhibition of succinate dehydrogenase and beta-hydroxybutyrate dehydrogenase activities by methylmalonate in brain and liver of developing rats. J Inherited Metab Dis 16:147–153

    Article  PubMed  CAS  Google Scholar 

  • Ferreira GC, Schuck PF, Viegas CM, Tonin A, Ribeiro CA, Pettenuzzo LF, Pereira LO, Netto CA, Wajner M (2008) Chronic early postnatal glutaric acid administration causes cognitive deficits in the water maze. Behav Brain Res 187(2):411–416. doi:10.1016/j.bbr.2007.10.003

    Article  CAS  Google Scholar 

  • Fiermonte G, Dolce V, David L, Santorelli FM, Dionisi-Vici C, Palmieri F, Walker JE (2003) The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. J Biol Chem 278(35):32778–32783

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo I (1994) Pharmacological evidence for a role of long-term potentiation in memory. FASEB J 8:1139–1145

    PubMed  CAS  Google Scholar 

  • Izquierdo I, Medina JH (1997) Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Mem 68:285–316

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo LA, Barros DM, Ardenghi PG, Pereira P, Rodrigues C, Choi H et al (2000) Different hippocampal molecular requirements for short- and long-term retrieval of one-trial avoidance learning. Behav Brain Res 111:93–98

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Kametani H (1988) Analysis of age related in stress-induced grooming in the rat. Ann N Y Acad Sci 525:101–113

    Article  PubMed  CAS  Google Scholar 

  • Mello CF, Somer JE, Tavaroni V, Graciolli R, Wu V, Torres G et al (1994) Effects of postnatal methylmalonate administration on neurobehavioral development of rats. Braz J Med Biol Res 27(3):655–661

    PubMed  CAS  Google Scholar 

  • Moreira JCF, Wannmacher CMD, Costa SM, Wajner M (1988) Effect of proline administration on rat behavior in the aversive and nonaversive tasks. Pharmacol Biochem Behav 32(4):885–890

    Article  Google Scholar 

  • Morris RGM, Garrud P, Rawlins JNP, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683

    Article  PubMed  CAS  Google Scholar 

  • Netto CA, Dias RD, Izquierdo I (1986) Differential effect of posttraining naloxone, beta-endorphin, leu-enkephalin and electroconvulsive shock administration upon memory of an open-field habituation and of a water-finding task. Psychoneuroendocrinology 11(4):437–446

    Article  PubMed  CAS  Google Scholar 

  • Netto CA, Hodges H, Sinden JD, Le Peillet E, Kershaw T, Sowinski P, Meldrum BS, Gray JA (1993) Effects of fetal hippocampal field grafts on ischaemic-induced deficits in spatial navigation in the water maze. Neuroscience 54:69–92

    Article  PubMed  CAS  Google Scholar 

  • O’Kane RL, Viña JR, Simpson I, Zaragozá R, Mokashi A, Hawkins RA (2006) Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+. Am J Physiol Endocrinol Metab 291(2):412–419. doi:10.1152/ajpendo.00007.2006

    Article  Google Scholar 

  • Palmieri F (2008) Diseases caused by defects of mitochondrial carriers: a review. Biochim Biophys Acta 1777(7–8):564–578. doi:10.1016/j.bbabio.2008.03.008

    PubMed  CAS  Google Scholar 

  • Pettenuzzo LF, Schuck PF, Fontella F, Wannmacher CMD, Wyse AT, Dutra-Filho CS, Netto CA, Wajner M (2002) Ascorbic acid prevents cognitive deficits caused by chronic administration of propionic acid to rats in the water maze. Pharmacol Biochem Behav 73:623–629

    Article  PubMed  CAS  Google Scholar 

  • Rodrigues AL, Rocha JB, Mello CF, Souza DO (1996) Effect of perinatal lead exposure on rat behaviour in open-field and two-way avoidance tasks. Pharmacol Toxicol 79:150–156

    Article  PubMed  CAS  Google Scholar 

  • Roisen FJ, Bartfeld H, Nagele R, Yorke G (1981) Gangliosides stimulation of axonal sprouting in vivo. Science 214:577–578

    Article  PubMed  CAS  Google Scholar 

  • Salvi S, Santorelli FM, Bertini E, Boldrini R, Meli C, Donati A, Burlina AB, Rizzo C, Di Capua M, Fariello G, Dionisi-Vici C (2001) Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 57:911–914

    Article  PubMed  CAS  Google Scholar 

  • Serrano F, Klann E (2004) Reactive oxygen species and synaptic plasticity in the aging hippocampus. Aging Res Ver 3(4):431–443

    Article  CAS  Google Scholar 

  • Shih VE, Efron ML, Moser HW (1969) Hyperornithinemia, hyperammonemia, and homocitrullinuria. A new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation. Am J Dis Child 117(1):83–92

    PubMed  CAS  Google Scholar 

  • Smart JL, Dobbing J (1971) Vulnerability of developing brain. II. Effect of early nutritional deprivation on reflex ontogeny and development of behavior in the rat. Brain Res 28:85–95

    Article  PubMed  CAS  Google Scholar 

  • Strupp BJ, Levitsky DA, Bluntein L (1984) PKU, learning and models of mental retardation. Dev Psychobiol 17:109–120

    Article  PubMed  CAS  Google Scholar 

  • Valle D, Simell O (2001) The hyperornithinemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited diseases. McGraw-Hill, New York, pp 1857–1896

    Google Scholar 

  • Vasques V, Brinco F, Viegas CM, Wajner M (2006) Creatine prevents behavioral alterations caused by methylmalonic acid administration into the hippocampus of rats in the open field task. J Neurol Sci 244(1–2):23–29. doi:10.1016/j.jns.2005.12.005

    Article  PubMed  CAS  Google Scholar 

  • Viegas CM, Zanatta A, Knebel LA, Schuck PF, Tonin AM, Ferreira Gda C, Amaral AU, Dutra Filho CS, Wannmacher CM, Wajner M (2009) Experimental evidence that ornithine and homocitrulline disrupt energy metabolism in brain of young rats. Brain Res 1291:102–112. doi:10.1016/j.brainres.2009.07.021

    Article  PubMed  CAS  Google Scholar 

  • Viegas CM, Busanello EN, Tonin AM, de Moura AP, Grings M, Ritter L, Schuck PF, Ferreira Gda C, Sitta A, Vargas CR, Wajner M (2011) Dual mechanism of brain damage induced in vivo by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Brain Res 19(1369):235–244. doi:10.1016/j.brainres.2010.10.112

    Article  Google Scholar 

  • Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 83:482–504

    Article  PubMed  CAS  Google Scholar 

  • Warren SG, Juraska JM (2000) Sex differences and estropausal phase effects on water maze performance in aged rats. Neurol Learn Mem 74:229–240

    Article  CAS  Google Scholar 

  • Yagi K (1998) Simple procedure for specific assay of lipid hydroperoxides in serum or plasma. Methods Mol Biol 108:107–110

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos, 2600 – Anexo, CEP: 90035-003, Porto Alegre, RS, Brazil

    Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Mateus Grings, Alana Pimentel Moura, Luciana Ritter, Ângela Zanatta, Lisiane Aurélio Knebel, Vannessa Araujo Lobato, Letícia Ferreira Pettenuzzo, Guilhian Leipnitz & Moacir Wajner

  2. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Carmen Regla Vargas & Moacir Wajner

Authors
  1. Carolina Maso Viegas
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  2. Estela Natacha Brandt Busanello
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  3. Anelise Miotti Tonin
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  4. Mateus Grings
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  5. Alana Pimentel Moura
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  6. Luciana Ritter
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  7. Ângela Zanatta
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  8. Lisiane Aurélio Knebel
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  9. Vannessa Araujo Lobato
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  10. Letícia Ferreira Pettenuzzo
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  11. Carmen Regla Vargas
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  12. Guilhian Leipnitz
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  13. Moacir Wajner
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Correspondence to Moacir Wajner.

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Viegas, C.M., Busanello, E.N.B., Tonin, A.M. et al. Chronic postnatal ornithine administration to rats provokes learning deficit in the open field task. Metab Brain Dis 27, 479–486 (2012). https://doi.org/10.1007/s11011-012-9322-x

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  • DOI: https://doi.org/10.1007/s11011-012-9322-x

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