Journal of Inherited Metabolic Disease

, Volume 36, Issue 4, pp 595–612 | Cite as

Ammonia toxicity to the brain

  • Olivier Braissant
  • Valérie A. McLin
  • Cristina Cudalbu


Hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle defects. The brain is much more susceptible to the deleterious effects of ammonium in childhood than in adulthood. Hyperammonemia provokes irreversible damage to the developing central nervous system: cortical atrophy, ventricular enlargement and demyelination lead to cognitive impairment, seizures and cerebral palsy. The mechanisms leading to these severe brain lesions are still not well understood, but recent studies show that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy metabolism, nitric oxide synthesis, oxidative stress and signal transduction pathways. All in all, at the cellular level, these are associated with alterations in neuronal differentiation and patterns of cell death. Recent advances in imaging techniques are increasing our understanding of these processes through detailed in vivo longitudinal analysis of neurobiochemical changes associated with hyperammonemia. Further, several potential neuroprotective strategies have been put forward recently, including the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine, acetyl-L-carnitine, CNTF or inhibitors of MAPKs and glutamine synthetase. Magnetic resonance imaging and spectroscopy will ultimately be a powerful tool to measure the effects of these neuroprotective approaches.


Hepatic Encephalopathy Glutamine Synthetase Arginase Acute Liver Failure Glutamine Synthetase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Olivier Braissant is supported by the Swiss National Science Foundation (grants n° 3100A0-100778 and 31003A-130278); Cristina Cudalbu is supported by the Centre d’Imagerie BioMédicale (CIBM - UNIL/UNIGE/HUG/CHUV/EPFL - Switzerland) as well as by the Leenaards and Jeantet Foundations; Valérie McLin is supported by the Department of Pediatrics, University of Geneva Medical School. The authors thank Dr B. Lanz for his help and expertise in 13C MRS, and Drs N. Kunz and Y. van de Looij for their help with DTI acquisitions.

Conflict of interest



  1. Aguilar MA, Minarro J, Felipo V (2000) Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats. Exp Neurol 161:704–713PubMedCrossRefGoogle Scholar
  2. Agusti A, Cauli O, Rodrigo R, Llansola M, Hernandez-Rabaza V, Felipo V (2011) p38 MAP kinase is a therapeutic target for hepatic encephalopathy in rats with portacaval shunts. Gut 60:1572–1579PubMedCrossRefGoogle Scholar
  3. Albrecht J, Norenberg MD (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44:788–794PubMedCrossRefGoogle Scholar
  4. Albrecht J, Zielinska M, Norenberg MD (2010) Glutamine as a mediator of ammonia neurotoxicity: a critical appraisal. Biochem Pharmacol 80:1303–1308PubMedCrossRefGoogle Scholar
  5. Als-Nielsen B, Gluud LL, Gluud C (2004) Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. Br Med J 328:1046CrossRefGoogle Scholar
  6. Alvarez VM, Rama Rao KV, Brahmbhatt M, Norenberg MD (2011) Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. J Neurosci Res 89:2028–2040PubMedCrossRefGoogle Scholar
  7. Azorin I, Minana MD, Felipo V, Grisolia S (1989) A simple animal model of hyperammonemia. Hepatology 10:311–314PubMedCrossRefGoogle Scholar
  8. Bachmann C (2003) Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 162:410–416PubMedCrossRefGoogle Scholar
  9. Bachmann C, Colombo JP (1984) Increase of tryptophan and 5-hydroxyindole acetic acid in the brain of ornithine carbamoyltransferase deficient sparse-fur mice. Pediatr Res 18:372–375PubMedCrossRefGoogle Scholar
  10. Bachmann C, Braissant O, Villard AM, Boulat O, Henry H (2004) Ammonia toxicity to the brain and creatine. Mol Genet Metab 81(Suppl 1):S52–S57PubMedCrossRefGoogle Scholar
  11. Bai G, Rama Rao KV, Murthy CR, Panickar KS, Jayakumar AR, Norenberg MD (2001) Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J Neurosci Res 66:981–991PubMedCrossRefGoogle Scholar
  12. Bajaj JS, Cordoba J, Mullen KD et al (2011) Review article: the design of clinical trials in hepatic encephalopathy–an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther 33:739–747PubMedCrossRefGoogle Scholar
  13. Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM (2012) Diagnosis and treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: a cost-effectiveness analysis. Hepatology 55:1164–1171PubMedCrossRefGoogle Scholar
  14. Bass NM, Mullen KD, Sanyal A et al (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362:1071–1081PubMedCrossRefGoogle Scholar
  15. Batshaw ML, MacArthur RB, Tuchman M (2001) Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 138:S46–S54PubMedCrossRefGoogle Scholar
  16. Béard E, Braissant O (2010) Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem 115:297–313PubMedCrossRefGoogle Scholar
  17. Bélanger M, Asashima T, Ohtsuki S, Yamaguchi H, Ito S, Terasaki T (2007) Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. Neurochem Int 50:95–101PubMedCrossRefGoogle Scholar
  18. Berl S, Takagaki G, Clarke DD, Waelsch H (1962) Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver. J Biol Chem 237:2562–2569PubMedGoogle Scholar
  19. Berry GT, Steiner RD (2001) Long-term management of patients with urea cycle disorders. J Pediatr 138:S56–S60PubMedCrossRefGoogle Scholar
  20. Bosoi CR, Yang X, Huynh J et al (2012) Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure. Free Radic Biol Med 52:1228–1235PubMedCrossRefGoogle Scholar
  21. Braissant O (2010a) Current concepts in the pathogenesis of urea cycle disorders. Mol Gen Metab 100(Suppl 1):S3–S12CrossRefGoogle Scholar
  22. Braissant O (2010b) Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine. Mol Genet Metab 100(Suppl 1):S53–S58PubMedCrossRefGoogle Scholar
  23. Braissant O (2012) Creatine and guanidinoacetate transport at blood–brain and blood-cerebrospinal fluid barriers. J Inherit Metab Dis 35:655–664PubMedCrossRefGoogle Scholar
  24. Braissant O, Gotoh T, Loup M, Mori M, Bachmann C (1999a) L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an in situ hybridization study. Mol Brain Res 70:231–241PubMedCrossRefGoogle Scholar
  25. Braissant O, Honegger P, Loup M, Iwase K, Takiguchi M, Bachmann C (1999b) Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate lyase genes in aggregating cell cultures of fetal rat brain. Neurosci Lett 266:89–92PubMedCrossRefGoogle Scholar
  26. Braissant O, Gotoh T, Loup M, Mori M, Bachmann C (2001) Differential expression of the cationic amino acid transporter 2(B) in the adult rat brain. Mol Brain Res 91:189–195PubMedCrossRefGoogle Scholar
  27. Braissant O, Henry H, Villard AM et al (2002) Ammonium-induced impairment of axonal growth is prevented through glial creatine. J Neurosci 22:9810–9820PubMedGoogle Scholar
  28. Braissant O, Cagnon L, Monnet-Tschudi F et al (2008) Ammonium alters creatine transport and synthesis in a 3D-culture of developing brain cells, resulting in secondary cerebral creatine deficiency. Eur J Neurosci 27:1673–1685PubMedCrossRefGoogle Scholar
  29. Braissant O, Henry H, Beard E, Uldry J (2011) Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 40:1315–1324PubMedCrossRefGoogle Scholar
  30. Brosnan JT, Brosnan ME (2010) Creatine metabolism and the urea cycle. Mol Genet Metab 100(Suppl 1):S49–S52PubMedCrossRefGoogle Scholar
  31. Brosnan ME, Edison EE, da Silva R, Brosnan JT (2007) New insights into creatine function and synthesis. Adv Enzym Regul 47:252–260CrossRefGoogle Scholar
  32. Brusilow SW, Maestri NE (1996) Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 43:127–170PubMedGoogle Scholar
  33. Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 2:452–454PubMedCrossRefGoogle Scholar
  34. Butterworth RF (1998) Effects of hyperammonaemia on brain function. J Inherit Metab Dis 21(Suppl 1):6–20PubMedCrossRefGoogle Scholar
  35. Butterworth RF (2003) Hepatic encephalopathy. Alcohol Res Health 27:240–246PubMedGoogle Scholar
  36. Butterworth RF (2012) Brain edema and encephalopathy in acute liver failure: a primary neurogliopathy? Neurochem Int 60:661PubMedCrossRefGoogle Scholar
  37. Butterworth RF, Norenberg MD, Felipo V et al (2009) Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 29:783–788PubMedCrossRefGoogle Scholar
  38. Cagnon L, Braissant O (2007) Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res Rev 56:183–197PubMedCrossRefGoogle Scholar
  39. Cagnon L, Braissant O (2008) Role of caspases, calpain and cdk5 in ammonia-induced cell death in developing brain cells. Neurobiol Dis 32:281–292PubMedCrossRefGoogle Scholar
  40. Cagnon L, Braissant O (2009) CNTF protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved. Neurobiol Dis 33:133–142PubMedCrossRefGoogle Scholar
  41. Call G, Seay AR, Sherry R, Qureshi IA (1984) Clinical features of carbamyl phosphate synthetase-I deficiency in an adult. Ann Neurol 16:90–93PubMedCrossRefGoogle Scholar
  42. Caudle SE, Katzenstein JM, Karpen SJ, McLin VA (2010) Language and motor skills are impaired in infants with biliary atresia before transplantation. J Pediatr 156:936–940PubMedCrossRefGoogle Scholar
  43. Caudle SE, Katzenstein JM, Karpen S, McLin V (2012) Developmental assessment of infants with biliary atresia: Differences between males and females. J Pediatr Gastroenterol Nutr 55(4):384-389Google Scholar
  44. Cauli O, Lopez-Larrubia P, Rodrigues TB, Cerdan S, Felipo V (2007) Magnetic resonance analysis of the effects of acute ammonia intoxication on rat brain. Role of NMDA receptors. J Neurochem 103:1334–1343PubMedCrossRefGoogle Scholar
  45. Cauli O, Rodrigo R, Llansola M et al (2009) Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy. Metab Brain Dis 24:69–80PubMedCrossRefGoogle Scholar
  46. Cauli O, Lopez-Larrubia P, Rodrigo R et al (2011) Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats. Gastroenterology 140:638–645PubMedCrossRefGoogle Scholar
  47. Cederbaum S, Lemons C, Batshaw ML (2010) Alternative pathway or diversion therapy for urea cycle disorders now and in the future. Mol Genet Metab 100:219–220PubMedCrossRefGoogle Scholar
  48. Chan H, Hazell AS, Desjardins P, Butterworth RF (2000) Effects of ammonia on glutamate transporter (GLAST) protein and mRNA in cultured rat cortical astrocytes. Neurochem Int 37:243–248PubMedCrossRefGoogle Scholar
  49. Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a 1H/13C-nuclear magnetic resonance study. Gastroenterology 125:815–824PubMedCrossRefGoogle Scholar
  50. Chavarria L, Oria M, Romero-Gimenez J, Alonso J, Lope-Piedrafita S, Cordoba J (2010) Diffusion tensor imaging supports the cytotoxic origin of brain edema in a rat model of acute liver failure. Gastroenterology 138:1566–1573PubMedCrossRefGoogle Scholar
  51. Chavarria L, Alonso J, Rovira A, Cordoba J (2011) Neuroimaging in acute liver failure. Neurochem Int 59:1175–1180PubMedCrossRefGoogle Scholar
  52. Chepkova AN, Sergeeva OA, Haas HL (2006) Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis 23:512–521PubMedCrossRefGoogle Scholar
  53. Choi JH, Kim H, Yoo HW (2006) Two cases of citrullinaemia presenting with stroke. J Inherit Metab Dis 29:182–183PubMedCrossRefGoogle Scholar
  54. Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, Leonard JV (1993) Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 33:77–81PubMedCrossRefGoogle Scholar
  55. Cordoba J (1996) Glutamine, myo-inositol, and brain edema in acute liver failure. Hepatology 23:1291–1292PubMedCrossRefGoogle Scholar
  56. Cordoba J, Blei AT (1996) Brain edema and hepatic encephalopathy. Semin Liver Dis 16:271–280PubMedCrossRefGoogle Scholar
  57. Cudalbu C, Mlynárik V, Lanz B, Frenkel H, Costers N, Gruetter R (2010) Imaging glutamine synthesis rates in the hyperammonemic rat brain. Proc Intl Soc Magn Reson Med 18:3324Google Scholar
  58. Cudalbu C, Mlynárik V, Gruetter R (2012a) Handling macromolecule signals in the quantification of the neurochemical profile. J Alzh Dis 31:S101-115Google Scholar
  59. Cudalbu C, Lanz B, Duarte JM et al (2012b) Cerebral glutamine metabolism under hyperammonemia determined in vivo by localized 1H and 15N NMR spectroscopy. J Cereb Blood Flow Metab 32:696–708PubMedCrossRefGoogle Scholar
  60. D’Hooge R, Marescau B, Qureshi IA, De Deyn PP (2000) Impaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet. Brain Res 876:1–9PubMedCrossRefGoogle Scholar
  61. Dadsetan S, Bak LK, Sørensen M et al (2011) Inhibition of glutamine synthesis induces glutamate dehydrogenase-dependent ammonia fixation into alanine in co-cultures of astrocytes and neurons. Neurochem Int 59:482–488PubMedCrossRefGoogle Scholar
  62. de Grauw TJ, Smit LM, Brockstedt M, Meijer Y, van der Klei-van Moorsel JM, Jakobs C (1990) Acute hemiparesis as the presenting sign in a heterozygote for ornithine transcarbamylase deficiency. Neuropediatrics 21:133–135PubMedCrossRefGoogle Scholar
  63. de Knegt RJ, Schalm SW, van der Rijt CC, Fekkes D, Dalm E, Hekking-Weyma I (1994) Extracellular brain glutamate during acute liver failure and during acute hyperammonemia simulating acute liver failure: an experimental study based on in vivo brain dialysis. J Hepatol 20:19–26PubMedCrossRefGoogle Scholar
  64. Deignan JL, Cederbaum SD, Grody WW (2008) Contrasting features of urea cycle disorders in human patients and knockout mouse models. Mol Genet Metab 93:7–14PubMedCrossRefGoogle Scholar
  65. Desjardins P, Du T, Jiang W, Peng L, Butterworth RF (2012) Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem Int 60:690–696PubMedCrossRefGoogle Scholar
  66. Dolder M, Walzel B, Speer O, Schlattner U, Wallimann T (2003) Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation. J Biol Chem 278:17760–17766PubMedCrossRefGoogle Scholar
  67. Dolman CL, Clasen RA, Dorovini-Zis K (1988) Severe cerebral damage in ornithine transcarbamylase deficiency. Clin Neuropathol 7:10–15PubMedGoogle Scholar
  68. Eltawil KM, Laryea M, Peltekian K, Molinari M (2012) Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol 18:767–777PubMedCrossRefGoogle Scholar
  69. Enns GM (2008) Neurologic damage and neurocognitive dysfunction in urea cycle disorders. Semin Pediatr Neurol 15:132–139PubMedCrossRefGoogle Scholar
  70. Enns GM (2010) Nitrogen sparing therapy revisited 2009. Mol Genet Metab 100(Suppl 1):S65–S71PubMedCrossRefGoogle Scholar
  71. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A (2007) Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 356:2282–2292PubMedCrossRefGoogle Scholar
  72. Felipo V, Grau E, Minana MD, Grisolia S (1993) Hyperammonemia decreases protein-kinase-C-dependent phosphorylation of microtubule-associated protein 2 and increases its binding to tubulin. Eur J Biochem 214:243–249PubMedCrossRefGoogle Scholar
  73. Felipo V, Ordono JF, Urios A et al (2012) Patients with minimal hepatic encephalopathy show impaired mismatch negativity correlating with reduced performance in attention tests. Hepatology 55:530–539PubMedCrossRefGoogle Scholar
  74. Filloux F, Townsend JJ, Leonard C (1986) Ornithine transcarbamylase deficiency: neuropathologic changes acquired in utero. J Pediatr 108:942–945PubMedCrossRefGoogle Scholar
  75. Fitzpatrick SM, Hetherington HP, Behar KL, Shulman RG (1989) Effects of acute hyperammonemia on cerebral amino acid metabolism and pHi in vivo, measured by 1H and 31P nuclear magnetic resonance. J Neurochem 52:741–749PubMedCrossRefGoogle Scholar
  76. Flint Beal M, Martin JB (1998) Major complications of cirrhosis. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL (eds) Harrison’s principles of internal medicine, 14th edn. McGraw-Hill, New-York, pp 2451–2457Google Scholar
  77. Foerster BR, Conklin LS, Petrou M, Barker PB, Schwarz KB (2009) Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy. Am J Neuroradiol 30:1610–1613PubMedCrossRefGoogle Scholar
  78. Garcia-Ayllon MS, Cauli O, Silveyra MX et al (2008) Brain cholinergic impairment in liver failure. Brain 131:2946–2956PubMedCrossRefGoogle Scholar
  79. Gropman A (2010) Brain imaging in urea cycle disorders. Mol Genet Metab 100(Suppl 1):S20–S30PubMedCrossRefGoogle Scholar
  80. Gropman AL, Summar M, Leonard JV (2007) Neurological implications of urea cycle disorders. J Inherit Metab Dis 30:865–879PubMedCrossRefGoogle Scholar
  81. Gropman AL, Gertz B, Shattuck K et al (2010) Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. Am J Neuroradiol 31:1719–1723PubMedCrossRefGoogle Scholar
  82. Grover VP, Dresner MA, Forton DM et al (2006) Current and future applications of magnetic resonance imaging and spectroscopy of the brain in hepatic encephalopathy. World J Gastroenterol 12:2969–2978PubMedGoogle Scholar
  83. Gruetter R (2002) In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism. Neurochem Int 41:143–154PubMedCrossRefGoogle Scholar
  84. Harada E, Nishiyori A, Tokunaga Y et al (2006) Late-onset ornithine transcarbamylase deficiency in male patients: prognostic factors and characteristics of plasma amino acid profile. Pediatr Int 48:105–111PubMedCrossRefGoogle Scholar
  85. Harding BN, Leonard JV, Erdohazi M (1984) Ornithine carbamoyl transferase deficiency: a neuropathological study. Eur J Pediatr 141:215–220PubMedCrossRefGoogle Scholar
  86. Harding BN, Leonard JV, Erdohazi M (1991) Propionic acidaemia: a neuropathological study of two patients presenting in infancy. Neuropathol Appl Neurobiol 17:133–138PubMedCrossRefGoogle Scholar
  87. Hertz L, Kala G (2007) Energy metabolism in brain cells: effects of elevated ammonia concentrations. Metab Brain Dis 22:199–218PubMedCrossRefGoogle Scholar
  88. Holm LM, Jahn TP, Møller AL et al (2005) NH3 and NH4 + permeability in aquaporin-expressing Xenopus oocytes. Pflugers Arch 450:415–428PubMedCrossRefGoogle Scholar
  89. Honegger P, Monnet-Tschudi F (2001) Aggregating neural cell culture. In: Fedoroff S, Richardson A (eds) Protocols for neural cell culture, 3rd edn. Humana Press, Totowa, pp 199–218CrossRefGoogle Scholar
  90. Hopkins KJ, McKean J, Mervis RF, Oster-Granite ML (1998) Dendritic alterations in cortical pyramidal cells in the sparse fur mouse. Brain Res 797:167–172PubMedCrossRefGoogle Scholar
  91. Hyman SL, Coyle JT, Parke JC et al (1986) Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria. J Pediatr 108:705–709PubMedCrossRefGoogle Scholar
  92. Hyman SL, Porter CA, Page TJ, Iwata BA, Kissel R, Batshaw ML (1987) Behavior management of feeding disturbances in urea cycle and organic acid disorders. J Pediatr 111:558–562PubMedCrossRefGoogle Scholar
  93. Inoue I, Gushiken T, Kobayashi K, Saheki T (1987) Accumulation of large neutral amino acids in the brain of sparse-fur mice at hyperammonemic state. Biochem Med Metab Biol 38:378–386PubMedCrossRefGoogle Scholar
  94. Izumi Y, Izumi M, Matsukawa M, Funatsu M, Zorumski CF (2005) Ammonia-mediated LTP inhibition: effects of NMDA receptor antagonists and L-carnitine. Neurobiol Dis 20:615–624PubMedCrossRefGoogle Scholar
  95. Jalan R, Wright G, Davies NA, Hodges SJ (2007) L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses 69:1064–1069PubMedCrossRefGoogle Scholar
  96. Jambekar AA, Palma E, Nicolosi L et al (2011) A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure. Liver Int 31:1209–1221PubMedCrossRefGoogle Scholar
  97. Jayakumar AR, Norenberg MD (2010) The Na-K-Cl Co-transporter in astrocyte swelling. Metab Brain Dis 25:31–38PubMedCrossRefGoogle Scholar
  98. Jayakumar AR, Panickar KS, Murthy C, Norenberg MD (2006) Oxidative stress and mitogen-activated protein kinase phosphorylation mediate ammonia-induced cell swelling and glutamate uptake inhibition in cultured astrocytes. J Neurosci 26:4774–4784PubMedCrossRefGoogle Scholar
  99. Jayakumar AR, Valdes V, Norenberg MD (2011) The Na-K-Cl cotransporter in the brain edema of acute liver failure. J Hepatol 54:272–278PubMedCrossRefGoogle Scholar
  100. Jayakumar AR, Tong XY, Ospel J, Norenberg MD (2012) Role of cerebral endothelial cells in the astrocyte swelling and brain edema associated with acute hepatic encephalopathy. Neuroscience 218:305–316PubMedCrossRefGoogle Scholar
  101. Kale RA, Gupta RK, Saraswat VA et al (2006) Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy. Hepatology 43:698–706PubMedCrossRefGoogle Scholar
  102. Kanamori K, Ross BD (1995) Steady-state in vivo glutamate dehydrogenase activity in rat brain measured by 15N NMR. J Biol Chem 270:24805–24809PubMedCrossRefGoogle Scholar
  103. Kanamori K, Parivar F, Ross BD (1993) A 15N NMR study of in vivo cerebral glutamine synthesis in hyperammonemic rats. NMR Biomed 6:21–26PubMedCrossRefGoogle Scholar
  104. Kim IS, Ki CS, Kim JW, Lee M, Jin DK, Lee SY (2006) Characterization of late-onset citrullinemia 1 in a Korean patient: confirmation by argininosuccinate synthetase gene mutation analysis. J Biochem Mol Biol 39:400–405PubMedCrossRefGoogle Scholar
  105. Kim MJ, Ko JS, Seo JK et al (2012) Clinical features of congenital portosystemic shunt in children. Eur J Pediatr 171:395–400PubMedCrossRefGoogle Scholar
  106. Kircheis G, Nilius R, Held C et al (1997) Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 25:1351–1360PubMedCrossRefGoogle Scholar
  107. Klejman A, Wegrzynowicz M, Szatmari EM, Mioduszewska B, Hetman M, Albrecht J (2005) Mechanisms of ammonia-induced cell death in rat cortical neurons: roles of NMDA receptors and glutathione. Neurochem Int 47:51–57PubMedCrossRefGoogle Scholar
  108. Kosenko E, Kaminsky Y, Kaminsky A et al (1997) Superoxide production and antioxidant enzymes in ammonia intoxication in rats. Free Radic Res 27:637–644PubMedCrossRefGoogle Scholar
  109. Kosenko E, Kaminsky Y, Lopata O et al (1998) Nitroarginine, an inhibitor of nitric oxide synthase, prevents changes in superoxide radical and antioxidant enzymes induced by ammonia intoxication. Metab Brain Dis 13:29–41PubMedCrossRefGoogle Scholar
  110. Kosenko E, Kaminski Y, Lopata O, Muravyov N, Felipo V (1999) Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radic Biol Med 26:1369–1374PubMedCrossRefGoogle Scholar
  111. Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML (2009) Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 66:96–101PubMedCrossRefGoogle Scholar
  112. Kurihara A, Takanashi J, Tomita M et al (2003) Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency. Brain Dev 25:40–44PubMedCrossRefGoogle Scholar
  113. Lai JC, Cooper AJ (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 47:1376–1386PubMedCrossRefGoogle Scholar
  114. Lanz B, Cudalbu C, Duarte JM, Gruetter R (2011) Direct assessment of increased pyruvate carboxylase in the hyperammonemic brain using 13C MRS. Proc Intl Soc Magn Reson Med 19:2256Google Scholar
  115. Le Bihan D (ed) (1995) Diffusion and perfusion magnetic resonance imaging: Applications to fonctional MRI. Raven, New YorkGoogle Scholar
  116. Lee B, Goss J (2001) Long-term correction of urea cycle disorders. J Pediatr 138:S62–S71PubMedCrossRefGoogle Scholar
  117. Leonard JV, Morris AA (2002) Urea cycle disorders. Semin Neonatol 7:27–35PubMedCrossRefGoogle Scholar
  118. Leonard JV, Ward Platt MP, Morris AA (2008) Hypothesis: proposals for the management of a neonate at risk of hyperammonaemia due to a urea cycle disorder. Eur J Pediatr 167:305–309PubMedCrossRefGoogle Scholar
  119. Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V (2008) Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia 56:365–377PubMedCrossRefGoogle Scholar
  120. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497PubMedCrossRefGoogle Scholar
  121. Majoie CB, Mourmans JM, Akkerman EM, Duran M, Poll-The BT (2004) Neonatal citrullinemia: comparison of conventional MR, diffusion-weighted, and diffusion tensor findings. Am J Neuroradiol 25:32–35PubMedGoogle Scholar
  122. Marcaida G, Minana MD, Grisolia S, Felipo V (1995) Lack of correlation between glutamate-induced depletion of ATP and neuronal death in primary cultures of cerebellum. Brain Res 695:146–150PubMedCrossRefGoogle Scholar
  123. McLin VA, Braissant O, van de Looij Y, Kunz N, Gruetter R, Cudalbu C (2012) Assessment of cerebral osmotic regulation in a rat model of biliary cirrhosis using MR spectroscopy. J Hepatol 56(Suppl 2):S231–S232CrossRefGoogle Scholar
  124. Mekle R, Mlynarik V, Gambarota G, Hergt M, Krueger G, Gruetter R (2009) MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3T and 7T. Magn Reson Med 61:1279–1285PubMedCrossRefGoogle Scholar
  125. Meyburg J, Hoffmann GF (2010) Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects. Mol Genet Metab 100(Suppl 1):S77–S83PubMedCrossRefGoogle Scholar
  126. Michalak A, Butterworth RF (1997) Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. Metab Brain Dis 12:171–182PubMedCrossRefGoogle Scholar
  127. Mlynarik V, Cudalbu C, Xin L, Gruetter R (2008a) 1H NMR spectroscopy of rat brain in vivo at 14.1Tesla: improvements in quantification of the neurochemical profile. J Magn Reson 194:163–168PubMedCrossRefGoogle Scholar
  128. Mlynarik V, Kohler I, Gambarota G, Vaslin A, Clarke PG, Gruetter R (2008b) Quantitative proton spectroscopic imaging of the neurochemical profile in rat brain with microliter resolution at ultra-short echo times. Magn Reson Med 59:52–58PubMedCrossRefGoogle Scholar
  129. Montoliu C, Gonzalez-Escamilla G, Atienza M et al (2012) Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy. NeuroImage 61:1165–1175PubMedCrossRefGoogle Scholar
  130. Moriyama M, Jayakumar AR, Tong XY, Norenberg MD (2010) Role of mitogen-activated protein kinases in the mechanism of oxidant-induced cell swelling in cultured astrocytes. J Neurosci Res 88:2450–2458PubMedGoogle Scholar
  131. Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED (1984) Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 310:1500–1505PubMedCrossRefGoogle Scholar
  132. Munoz MD, Monfort P, Gaztelu JM, Felipo V (2000) Hyperammonemia impairs NMDA receptor-dependent long-term potentiation in the CA1 of rat hippocampus in vitro. Neurochem Res 25:437–441PubMedCrossRefGoogle Scholar
  133. Murthy CR, Rama Rao KV, Bai G, Norenberg MD (2001) Ammonia-induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 66:282–288PubMedCrossRefGoogle Scholar
  134. Nagasaka H, Komatsu H, Ohura T et al (2004) Nitric oxide synthesis in ornithine transcarbamylase deficiency: possible involvement of low NO synthesis in clinical manifestations of urea cycle defect. J Pediatr 145:259–262PubMedCrossRefGoogle Scholar
  135. Norenberg MD, Rao KV, Jayakumar AR (2005) Mechanisms of ammonia-induced astrocyte swelling. Metab Brain Dis 20:303–318PubMedCrossRefGoogle Scholar
  136. Nyberg SL, Cerra FB, Gruetter R (1998) Brain lactate by magnetic resonance spectroscopy during fulminant hepatic failure in the dog. Liver Transp Surg 4:158–165CrossRefGoogle Scholar
  137. Obara-Michlewska M, Pannicke T, Karl A et al (2011) Down-regulation of Kir4.1 in the cerebral cortex of rats with liver failure and in cultured astrocytes treated with glutamine: Implications for astrocytic dysfunction in hepatic encephalopathy. J Neurosci Res 89:2018–2027PubMedCrossRefGoogle Scholar
  138. Olde Damink SW, Deutz NE, Dejong CH, Soeters PB, Jalan R (2002) Interorgan ammonia metabolism in liver failure. Neurochem Int 41:177–188PubMedCrossRefGoogle Scholar
  139. Oldham MS, vanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL (2010) Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol 42:49–52PubMedCrossRefGoogle Scholar
  140. Oria M, Romero-Giménez J, Arranz JA, Riudor E, Raquer N, Córdoba J (2012) Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis. J Hepatol 56:109–114PubMedCrossRefGoogle Scholar
  141. Panickar KS, Jayakumar AR, Rao KV, Norenberg MD (2009) Ammonia-induced activation of p53 in cultured astrocytes: role in cell swelling and glutamate uptake. Neurochem Int 55:98–105PubMedCrossRefGoogle Scholar
  142. Patil DH, Westaby D, Mahida YR et al (1987) Comparative modes of action of lactitol and lactulose in the treatment of hepatic encephalopathy. Gut 28:255–259PubMedCrossRefGoogle Scholar
  143. Pfeuffer J, Tkác I, Provencher SW, Gruetter R (1999) Toward an in vivo neurochemical profile: quantification of 18 metabolites in short-echo-time 1H NMR spectra of the rat brain. J Magn Reson 141:104–120PubMedCrossRefGoogle Scholar
  144. Pietrobattista A, Luciani M, Abraldes JG et al (2010) Extrahepatic portal vein thrombosis in children and adolescents: influence of genetic Thrombophilic disorders. World J Gastroenterol 16:6123–6127PubMedCrossRefGoogle Scholar
  145. Qureshi IA, Rao KV (1997) Sparse-fur (spf) mouse as a model of hyperammonemia: alterations in the neurotransmitter systems. Adv Exp Med Biol 420:143–158PubMedCrossRefGoogle Scholar
  146. Rama Rao KV, Jayakumar AR, Tong X, Curtis KM, Norenberg MD (2010) Brain aquaporin-4 in experimental acute liver failure. J Neuropathol Exp Neurol 69:869–879PubMedCrossRefGoogle Scholar
  147. Rama Rao KV, Jayakumar AR, Norenberg MD (2012) Glutamine in the pathogenesis of acute hepatic encephalopathy. Neurochem Int 61:575–580PubMedCrossRefGoogle Scholar
  148. Ranjan P, Mishra AM, Kale R, Saraswat VA, Gupta RK (2005) Cytotoxic edema is responsible for raised intracranial pressure in fulminant hepatic failure: in vivo demonstration using diffusion-weighted MRI in human subjects. Metab Brain Dis 20:181–192PubMedCrossRefGoogle Scholar
  149. Rao VLR (2002) Nitric oxide in hepatic encephalopathy and hyperammonemia. Neurochem Int 41:161–170PubMedCrossRefGoogle Scholar
  150. Rao KV, Qureshi IA (1999) Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl-L-carnitine. Neuropharmacology 38:383–394PubMedCrossRefGoogle Scholar
  151. Rao KV, Mawal YR, Qureshi IA (1997) Progressive decrease of cerebral cytochrome C oxidase activity in sparse-fur mice: role of acetyl-L-carnitine in restoring the ammonia-induced cerebral energy depletion. Neurosci Lett 224:83–86PubMedCrossRefGoogle Scholar
  152. Ratnakumari L, Qureshi IA, Butterworth RF (1992) Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice. Biochem Biophys Res Commun 184:746–751PubMedCrossRefGoogle Scholar
  153. Ratnakumari L, Qureshi IA, Butterworth RF (1994a) Regional amino acid neurotransmitter changes in brains of spf/Y mice with congenital ornithine transcarbamylase deficiency. Metab Brain Dis 9:43–51PubMedCrossRefGoogle Scholar
  154. Ratnakumari L, Qureshi IA, Butterworth RF (1994b) Evidence for cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency. Neurosci Lett 178:63–65PubMedCrossRefGoogle Scholar
  155. Ratnakumari L, Qureshi IA, Maysinger D, Butterworth RF (1995) Developmental deficiency of the cholinergic system in congenitally hyperammonemic spf mice: effect of acetyl-L-carnitine. J Pharmacol Exp Ther 274:437–443PubMedGoogle Scholar
  156. Ratnakumari L, Qureshi IA, Butterworth RF (1996a) Central muscarinic cholinergic M1 and M2 receptor changes in congenital ornithine transcarbamylase deficiency. Pediatr Res 40:25–28PubMedCrossRefGoogle Scholar
  157. Ratnakumari L, Qureshi IA, Butterworth RF, Marescau B, De Deyn PP (1996b) Arginine-related guanidino compounds and nitric oxide synthase in the brain of ornithine transcarbamylase deficient spf mutant mouse: effect of metabolic arginine deficiency. Neurosci Lett 215:153–156PubMedCrossRefGoogle Scholar
  158. Reinehr R, Gorg B, Becker S et al (2007) Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices. Glia 55:758–771PubMedCrossRefGoogle Scholar
  159. Robinson MB, Anegawa NJ, Gorry E et al (1992a) Brain serotonin2 and serotonin1A receptors are altered in the congenitally hyperammonemic sparse fur mouse. J Neurochem 58:1016–1022PubMedCrossRefGoogle Scholar
  160. Robinson MB, Heyes MP, Anegawa NJ et al (1992b) Quinolinate in brain and cerebrospinal fluid in rat models of congenital hyperammonemia. Pediatr Res 32:483–488PubMedCrossRefGoogle Scholar
  161. Rodrigo R, Erceg S, Felipo V (2005) Neurons exposed to ammonia reproduce the differential alteration in nitric oxide modulation of guanylate cyclase in the cerebellum and cortex of patients with liver cirrhosis. Neurobiol Dis 19:150–161PubMedCrossRefGoogle Scholar
  162. Rodrigo R, Cauli O, Boix J, El Mlili N, Agusti A, Felipo V (2009) Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications. Neurochem Int 55:113–118PubMedCrossRefGoogle Scholar
  163. Rose C (2006) Effect of ammonia on astrocytic glutamate uptake/release mechanisms. J Neurochem 97(Suppl 1):11–15PubMedCrossRefGoogle Scholar
  164. Rose C, Felipo V (2005) Limited capacity for ammonia removal by brain in chronic liver failure: potential role of nitric oxide. Metab Brain Dis 20:275–283PubMedCrossRefGoogle Scholar
  165. Rose C, Michalak A, Pannunzio P et al (1998) L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action. Metab Brain Dis 13:147–157PubMedCrossRefGoogle Scholar
  166. Rose C, Kresse W, Kettenmann H (2005) Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH. J Biol Chem 280:20937–20944PubMedCrossRefGoogle Scholar
  167. Rovira A, Alonso J, Cordoba J (2008) MR imaging findings in hepatic encephalopathy. Am J Neuroradiol 29:1612–1621PubMedCrossRefGoogle Scholar
  168. Salvi S, Santorelli FM, Bertini E et al (2001) Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 57:911–914PubMedCrossRefGoogle Scholar
  169. Scaglia F (2010) New insights in nutritional management and amino acid supplementation in urea cycle disorders. Mol Genet Metab 100(Suppl 1):S72–S76PubMedCrossRefGoogle Scholar
  170. Scaglia F, Lee B (2006) Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C Semin Med Genet 142:113–120Google Scholar
  171. Scaglia F, Zheng Q, O'Brien WE et al (2002) An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency. Pediatrics 109:150–152PubMedCrossRefGoogle Scholar
  172. Scaglia F, Brunetti-Pierri N, Kleppe S et al (2004) Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr 134:2775S–2782SPubMedGoogle Scholar
  173. Schliess F, Gorg B, Fischer R et al (2002) Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J 16:739–741PubMedGoogle Scholar
  174. Shen J, Sibson NR, Cline G, Behar KL, Rothman DL, Shulman RG (1998) 15N-NMR spectroscopy studies of ammonia transport and glutamine synthesis in the hyperammonemic rat brain. Dev Neurosci 20:434–443PubMedCrossRefGoogle Scholar
  175. Shih VE (2007) Alternative-pathway therapy for hyperammonemia. N Engl J Med 356:2321–2322PubMedCrossRefGoogle Scholar
  176. Sibson NR, Dhankhar A, Mason GF, Behar KL, Rothman DL, Shulman RG (1997) In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling. Proc Natl Acad Sci USA 94:2699–2704PubMedCrossRefGoogle Scholar
  177. Sibson NR, Mason GF, Shen J et al (2001) In vivo 13C NMR measurement of neurotransmitter glutamate cycling, anaplerosis and TCA cycle flux in rat brain during [2-13C]glucose infusion. J Neurochem 76:975–989PubMedCrossRefGoogle Scholar
  178. Skowronska M, Zielinska M, Wojcik-Stanaszek L et al (2012) Ammonia increases paracellular permeability of rat brain endothelial cells by a mechanism encompassing oxidative/nitrosative stress and activation of matrix metalloproteinases. J Neurochem 121:125–134PubMedCrossRefGoogle Scholar
  179. Smith W, Kishnani PS, Lee B et al (2005) Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin 21:S9–S17PubMedCrossRefGoogle Scholar
  180. Song G, Dhodda VK, Blei AT, Dempsey RJ, Rao VL (2002) GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of portacaval shunted rats. J Neurosci Res 68:730–737PubMedCrossRefGoogle Scholar
  181. Spahr L, Burkhard PR, Grotzsch H, Hadengue A (2002) Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in cirrhosis and role in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 17:399–413PubMedCrossRefGoogle Scholar
  182. Summar M (2001) Current strategies for the management of neonatal urea cycle disorders. J Pediatr 138:S30–S39PubMedCrossRefGoogle Scholar
  183. Takanashi J, Kurihara A, Tomita M et al (2002) Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency. Neurology 59:210–214PubMedCrossRefGoogle Scholar
  184. Takanashi J, Barkovich AJ, Cheng SF et al (2003) Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. Am J Neuroradiol 24:1184–1187PubMedGoogle Scholar
  185. Takeoka M, Soman TB, Shih VE, Caviness VS, Krishnamoorthy KS (2001) Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy. Pediatr Neurol 24:193–199PubMedCrossRefGoogle Scholar
  186. Tanigami H, Rebel A, Martin LJ et al (2005) Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats. Neuroscience 131:437–449PubMedCrossRefGoogle Scholar
  187. Tkác I, Starcuk Z, Choi IY, Gruetter R (1999) In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time. Magn Reson Med 41:649–656PubMedCrossRefGoogle Scholar
  188. Tkác I, Oz G, Adriany G, Ugurbil K, Gruetter R (2009) In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magn Reson Med 62:868–879PubMedCrossRefGoogle Scholar
  189. Tuchman M, Lee B, Lichter-Konecki U et al (2008) Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab 94:397–402PubMedCrossRefGoogle Scholar
  190. Uchino T, Endo F, Matsuda I (1998) Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis 21(Suppl 1):151–159PubMedCrossRefGoogle Scholar
  191. Veres G, Gibbs RA, Scherer SE, Caskey CT (1987) The molecular basis of the sparse fur mouse mutation. Science 237:415–417PubMedCrossRefGoogle Scholar
  192. Walker V (2009) Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 11:823–835PubMedCrossRefGoogle Scholar
  193. Wiesinger H (2001) Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol 64:365–391PubMedCrossRefGoogle Scholar
  194. Willard-Mack CL, Koehler RC, Hirata T et al (1996) Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 71:589–599PubMedCrossRefGoogle Scholar
  195. Wright G, Vairappan B, Stadlbauer V, Mookerjee RP, Davies NA, Jalan R (2012) Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats. Liver Int 32:410–419PubMedGoogle Scholar
  196. Yadav SK, Srivastava A, Thomas MA et al (2010) Encephalopathy assessment in children with extra-hepatic portal vein obstruction with MR, psychometry and critical flicker frequency. J Hepatol 52:348–354PubMedCrossRefGoogle Scholar
  197. Yamanouchi H, Yokoo H, Yuhara Y et al (2002) An autopsy case of ornithine transcarbamylase deficiency. Brain Dev 24:91–94PubMedCrossRefGoogle Scholar
  198. Zanelli SA, Solenski NJ, Rosenthal RE, Fiskum G (2005) Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Ann N Y Acad Sci 1053:153–161PubMedCrossRefGoogle Scholar
  199. Zielinska M, Ruszkiewicz J, Hilgier W, Fresko I, Albrecht J (2011) Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y+ LAT2 in rat cerebral cortex: implications for the nitric oxide/cGMP pathway. Neurochem Int 58:190–195PubMedCrossRefGoogle Scholar
  200. Zielinska M, Skowronska M, Fresko I, Albrecht J (2012) Upregulation of the heteromeric y(+)LAT2 transporter contributes to ammonia-induced increase of arginine uptake in rat cerebral cortical astrocytes. Neurochem Int 61:531–535PubMedCrossRefGoogle Scholar
  201. Zwingmann C (2007) The anaplerotic flux and ammonia detoxification in hepatic encephalopathy. Metab Brain Dis 22:235–249PubMedCrossRefGoogle Scholar
  202. Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [1H-13C] nuclear magnetic resonance study. Hepatology 37:420–428PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Olivier Braissant
    • 1
  • Valérie A. McLin
    • 2
  • Cristina Cudalbu
    • 3
  1. 1.Service of BiomedicineLausanne University HospitalLausanneSwitzerland
  2. 2.Pediatric Gastroenterology Unit, Division of Pediatric Specialties, Department of Child and AdolescentUniversity Hospitals of Geneva (HUG)GenevaSwitzerland
  3. 3.Laboratory for Functional and Metabolic Imaging (LIFMET)Ecole Polytechnique Fédérale de Lausanne (EPFL)LausanneSwitzerland

Personalised recommendations