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Ammonia toxicity to the brain

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  • Published:
Journal of Inherited Metabolic Disease

Abstract

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.

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References

  • Aguilar MA, Minarro J, Felipo V (2000) Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats. Exp Neurol 161:704–713

    Article  PubMed  CAS  Google Scholar 

  • 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 60:1572–1579

    Article  PubMed  CAS  Google Scholar 

  • Albrecht J, Norenberg MD (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44:788–794

    Article  PubMed  CAS  Google Scholar 

  • Albrecht J, Zielinska M, Norenberg MD (2010) Glutamine as a mediator of ammonia neurotoxicity: a critical appraisal. Biochem Pharmacol 80:1303–1308

    Article  PubMed  CAS  Google Scholar 

  • Als-Nielsen B, Gluud LL, Gluud C (2004) Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. Br Med J 328:1046

    Article  CAS  Google Scholar 

  • 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 89:2028–2040

    Article  PubMed  CAS  Google Scholar 

  • Azorin I, Minana MD, Felipo V, Grisolia S (1989) A simple animal model of hyperammonemia. Hepatology 10:311–314

    Article  PubMed  CAS  Google Scholar 

  • Bachmann C (2003) Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 162:410–416

    Article  PubMed  CAS  Google Scholar 

  • 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 18:372–375

    Article  PubMed  CAS  Google Scholar 

  • 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–S57

    Article  PubMed  CAS  Google Scholar 

  • 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 66:981–991

    Article  PubMed  CAS  Google Scholar 

  • 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 33:739–747

    Article  PubMed  CAS  Google Scholar 

  • 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 55:1164–1171

    Article  PubMed  Google Scholar 

  • Bass NM, Mullen KD, Sanyal A et al (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362:1071–1081

    Article  PubMed  CAS  Google Scholar 

  • Batshaw ML, MacArthur RB, Tuchman M (2001) Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 138:S46–S54

    Article  PubMed  CAS  Google Scholar 

  • Béard E, Braissant O (2010) Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem 115:297–313

    Article  PubMed  CAS  Google Scholar 

  • 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 50:95–101

    Article  PubMed  CAS  Google Scholar 

  • 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 237:2562–2569

    PubMed  CAS  Google Scholar 

  • Berry GT, Steiner RD (2001) Long-term management of patients with urea cycle disorders. J Pediatr 138:S56–S60

    Article  PubMed  CAS  Google Scholar 

  • 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 52:1228–1235

    Article  PubMed  CAS  Google Scholar 

  • Braissant O (2010a) Current concepts in the pathogenesis of urea cycle disorders. Mol Gen Metab 100(Suppl 1):S3–S12

    Article  CAS  Google Scholar 

  • 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–S58

    Article  PubMed  CAS  Google Scholar 

  • Braissant O (2012) Creatine and guanidinoacetate transport at blood–brain and blood-cerebrospinal fluid barriers. J Inherit Metab Dis 35:655–664

    Article  PubMed  CAS  Google Scholar 

  • 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 70:231–241

    Article  PubMed  CAS  Google Scholar 

  • 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 266:89–92

    Article  PubMed  CAS  Google Scholar 

  • 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 91:189–195

    Article  PubMed  CAS  Google Scholar 

  • Braissant O, Henry H, Villard AM et al (2002) Ammonium-induced impairment of axonal growth is prevented through glial creatine. J Neurosci 22:9810–9820

    PubMed  CAS  Google Scholar 

  • 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 27:1673–1685

    Article  PubMed  Google Scholar 

  • Braissant O, Henry H, Beard E, Uldry J (2011) Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 40:1315–1324

    Article  PubMed  CAS  Google Scholar 

  • Brosnan JT, Brosnan ME (2010) Creatine metabolism and the urea cycle. Mol Genet Metab 100(Suppl 1):S49–S52

    Article  PubMed  CAS  Google Scholar 

  • Brosnan ME, Edison EE, da Silva R, Brosnan JT (2007) New insights into creatine function and synthesis. Adv Enzym Regul 47:252–260

    Article  CAS  Google Scholar 

  • Brusilow SW, Maestri NE (1996) Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 43:127–170

    PubMed  CAS  Google Scholar 

  • Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 2:452–454

    Article  PubMed  CAS  Google Scholar 

  • Butterworth RF (1998) Effects of hyperammonaemia on brain function. J Inherit Metab Dis 21(Suppl 1):6–20

    Article  PubMed  Google Scholar 

  • Butterworth RF (2003) Hepatic encephalopathy. Alcohol Res Health 27:240–246

    PubMed  Google Scholar 

  • Butterworth RF (2012) Brain edema and encephalopathy in acute liver failure: a primary neurogliopathy? Neurochem Int 60:661

    Article  PubMed  CAS  Google Scholar 

  • Butterworth RF, Norenberg MD, Felipo V et al (2009) Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 29:783–788

    Article  PubMed  Google Scholar 

  • Cagnon L, Braissant O (2007) Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res Rev 56:183–197

    Article  PubMed  CAS  Google Scholar 

  • Cagnon L, Braissant O (2008) Role of caspases, calpain and cdk5 in ammonia-induced cell death in developing brain cells. Neurobiol Dis 32:281–292

    Article  PubMed  CAS  Google Scholar 

  • Cagnon L, Braissant O (2009) CNTF protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved. Neurobiol Dis 33:133–142

    Article  PubMed  CAS  Google Scholar 

  • Call G, Seay AR, Sherry R, Qureshi IA (1984) Clinical features of carbamyl phosphate synthetase-I deficiency in an adult. Ann Neurol 16:90–93

    Article  PubMed  CAS  Google Scholar 

  • Caudle SE, Katzenstein JM, Karpen SJ, McLin VA (2010) Language and motor skills are impaired in infants with biliary atresia before transplantation. J Pediatr 156:936–940

    Article  PubMed  Google Scholar 

  • 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):384-389

    Google Scholar 

  • 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 103:1334–1343

    Article  PubMed  CAS  Google Scholar 

  • Cauli O, Rodrigo R, Llansola M et al (2009) Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy. Metab Brain Dis 24:69–80

    Article  PubMed  CAS  Google Scholar 

  • 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 140:638–645

    Article  PubMed  CAS  Google Scholar 

  • Cederbaum S, Lemons C, Batshaw ML (2010) Alternative pathway or diversion therapy for urea cycle disorders now and in the future. Mol Genet Metab 100:219–220

    Article  PubMed  CAS  Google Scholar 

  • 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 37:243–248

    Article  PubMed  CAS  Google Scholar 

  • 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 125:815–824

    Article  PubMed  CAS  Google Scholar 

  • 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 138:1566–1573

    Article  PubMed  CAS  Google Scholar 

  • Chavarria L, Alonso J, Rovira A, Cordoba J (2011) Neuroimaging in acute liver failure. Neurochem Int 59:1175–1180

    Article  PubMed  CAS  Google Scholar 

  • Chepkova AN, Sergeeva OA, Haas HL (2006) Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis 23:512–521

    Article  PubMed  CAS  Google Scholar 

  • Choi JH, Kim H, Yoo HW (2006) Two cases of citrullinaemia presenting with stroke. J Inherit Metab Dis 29:182–183

    Article  PubMed  CAS  Google Scholar 

  • 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 33:77–81

    Article  PubMed  CAS  Google Scholar 

  • Cordoba J (1996) Glutamine, myo-inositol, and brain edema in acute liver failure. Hepatology 23:1291–1292

    Article  PubMed  CAS  Google Scholar 

  • Cordoba J, Blei AT (1996) Brain edema and hepatic encephalopathy. Semin Liver Dis 16:271–280

    Article  PubMed  CAS  Google Scholar 

  • 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 18:3324

    Google Scholar 

  • Cudalbu C, Mlynárik V, Gruetter R (2012a) Handling macromolecule signals in the quantification of the neurochemical profile. J Alzh Dis 31:S101-115

    Google Scholar 

  • 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 32:696–708

    Article  PubMed  CAS  Google Scholar 

  • 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 876:1–9

    Article  PubMed  Google Scholar 

  • 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 59:482–488

    Article  PubMed  CAS  Google Scholar 

  • 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 21:133–135

    Article  PubMed  Google Scholar 

  • 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 20:19–26

    Article  PubMed  Google Scholar 

  • Deignan JL, Cederbaum SD, Grody WW (2008) Contrasting features of urea cycle disorders in human patients and knockout mouse models. Mol Genet Metab 93:7–14

    Article  PubMed  CAS  Google Scholar 

  • 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 60:690–696

    Article  PubMed  CAS  Google Scholar 

  • 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 278:17760–17766

    Article  PubMed  CAS  Google Scholar 

  • Dolman CL, Clasen RA, Dorovini-Zis K (1988) Severe cerebral damage in ornithine transcarbamylase deficiency. Clin Neuropathol 7:10–15

    PubMed  CAS  Google Scholar 

  • Eltawil KM, Laryea M, Peltekian K, Molinari M (2012) Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol 18:767–777

    Article  PubMed  CAS  Google Scholar 

  • Enns GM (2008) Neurologic damage and neurocognitive dysfunction in urea cycle disorders. Semin Pediatr Neurol 15:132–139

    Article  PubMed  Google Scholar 

  • Enns GM (2010) Nitrogen sparing therapy revisited 2009. Mol Genet Metab 100(Suppl 1):S65–S71

    Article  PubMed  CAS  Google Scholar 

  • 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 356:2282–2292

    Article  PubMed  CAS  Google Scholar 

  • 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 214:243–249

    Article  PubMed  CAS  Google Scholar 

  • 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 55:530–539

    Article  PubMed  Google Scholar 

  • Filloux F, Townsend JJ, Leonard C (1986) Ornithine transcarbamylase deficiency: neuropathologic changes acquired in utero. J Pediatr 108:942–945

    Article  PubMed  CAS  Google Scholar 

  • 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 52:741–749

    Article  PubMed  CAS  Google Scholar 

  • 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 2451–2457

    Google Scholar 

  • Foerster BR, Conklin LS, Petrou M, Barker PB, Schwarz KB (2009) Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy. Am J Neuroradiol 30:1610–1613

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Ayllon MS, Cauli O, Silveyra MX et al (2008) Brain cholinergic impairment in liver failure. Brain 131:2946–2956

    Article  PubMed  Google Scholar 

  • Gropman A (2010) Brain imaging in urea cycle disorders. Mol Genet Metab 100(Suppl 1):S20–S30

    Article  PubMed  CAS  Google Scholar 

  • Gropman AL, Summar M, Leonard JV (2007) Neurological implications of urea cycle disorders. J Inherit Metab Dis 30:865–879

    Article  PubMed  CAS  Google Scholar 

  • 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 31:1719–1723

    Article  PubMed  CAS  Google Scholar 

  • 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 12:2969–2978

    PubMed  CAS  Google Scholar 

  • Gruetter R (2002) In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism. Neurochem Int 41:143–154

    Article  PubMed  CAS  Google Scholar 

  • 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 48:105–111

    Article  PubMed  CAS  Google Scholar 

  • Harding BN, Leonard JV, Erdohazi M (1984) Ornithine carbamoyl transferase deficiency: a neuropathological study. Eur J Pediatr 141:215–220

    Article  PubMed  CAS  Google Scholar 

  • Harding BN, Leonard JV, Erdohazi M (1991) Propionic acidaemia: a neuropathological study of two patients presenting in infancy. Neuropathol Appl Neurobiol 17:133–138

    Article  PubMed  CAS  Google Scholar 

  • Hertz L, Kala G (2007) Energy metabolism in brain cells: effects of elevated ammonia concentrations. Metab Brain Dis 22:199–218

    Article  PubMed  CAS  Google Scholar 

  • Holm LM, Jahn TP, Møller AL et al (2005) NH3 and NH4 + permeability in aquaporin-expressing Xenopus oocytes. Pflugers Arch 450:415–428

    Article  PubMed  CAS  Google Scholar 

  • 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 199–218

    Chapter  Google Scholar 

  • Hopkins KJ, McKean J, Mervis RF, Oster-Granite ML (1998) Dendritic alterations in cortical pyramidal cells in the sparse fur mouse. Brain Res 797:167–172

    Article  PubMed  CAS  Google Scholar 

  • Hyman SL, Coyle JT, Parke JC et al (1986) Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria. J Pediatr 108:705–709

    Article  PubMed  CAS  Google Scholar 

  • 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 111:558–562

    Article  PubMed  CAS  Google Scholar 

  • 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 38:378–386

    Article  PubMed  CAS  Google Scholar 

  • 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 20:615–624

    Article  PubMed  CAS  Google Scholar 

  • Jalan R, Wright G, Davies NA, Hodges SJ (2007) L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses 69:1064–1069

    Article  PubMed  CAS  Google Scholar 

  • 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 31:1209–1221

    Article  PubMed  CAS  Google Scholar 

  • Jayakumar AR, Norenberg MD (2010) The Na-K-Cl Co-transporter in astrocyte swelling. Metab Brain Dis 25:31–38

    Article  PubMed  CAS  Google Scholar 

  • 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 26:4774–4784

    Article  PubMed  CAS  Google Scholar 

  • Jayakumar AR, Valdes V, Norenberg MD (2011) The Na-K-Cl cotransporter in the brain edema of acute liver failure. J Hepatol 54:272–278

    Article  PubMed  CAS  Google Scholar 

  • 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 218:305–316

    Article  PubMed  CAS  Google Scholar 

  • 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 43:698–706

    Article  PubMed  Google Scholar 

  • Kanamori K, Ross BD (1995) Steady-state in vivo glutamate dehydrogenase activity in rat brain measured by 15N NMR. J Biol Chem 270:24805–24809

    Article  PubMed  CAS  Google Scholar 

  • Kanamori K, Parivar F, Ross BD (1993) A 15N NMR study of in vivo cerebral glutamine synthesis in hyperammonemic rats. NMR Biomed 6:21–26

    Article  PubMed  CAS  Google Scholar 

  • 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 39:400–405

    Article  PubMed  CAS  Google Scholar 

  • Kim MJ, Ko JS, Seo JK et al (2012) Clinical features of congenital portosystemic shunt in children. Eur J Pediatr 171:395–400

    Article  PubMed  Google Scholar 

  • 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 25:1351–1360

    Article  PubMed  CAS  Google Scholar 

  • 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 47:51–57

    Article  PubMed  CAS  Google Scholar 

  • Kosenko E, Kaminsky Y, Kaminsky A et al (1997) Superoxide production and antioxidant enzymes in ammonia intoxication in rats. Free Radic Res 27:637–644

    Article  PubMed  CAS  Google Scholar 

  • 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 13:29–41

    Article  PubMed  CAS  Google Scholar 

  • 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 26:1369–1374

    Article  PubMed  CAS  Google Scholar 

  • 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 66:96–101

    Article  PubMed  CAS  Google Scholar 

  • Kurihara A, Takanashi J, Tomita M et al (2003) Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency. Brain Dev 25:40–44

    Article  PubMed  Google Scholar 

  • Lai JC, Cooper AJ (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 47:1376–1386

    Article  PubMed  CAS  Google Scholar 

  • 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 19:2256

    Google Scholar 

  • Le Bihan D (ed) (1995) Diffusion and perfusion magnetic resonance imaging: Applications to fonctional MRI. Raven, New York

    Google Scholar 

  • Lee B, Goss J (2001) Long-term correction of urea cycle disorders. J Pediatr 138:S62–S71

    Article  PubMed  CAS  Google Scholar 

  • Leonard JV, Morris AA (2002) Urea cycle disorders. Semin Neonatol 7:27–35

    Article  PubMed  CAS  Google Scholar 

  • 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 167:305–309

    Article  PubMed  Google Scholar 

  • 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 56:365–377

    Article  PubMed  Google Scholar 

  • Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497

    Article  PubMed  CAS  Google Scholar 

  • 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 25:32–35

    PubMed  Google Scholar 

  • 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 695:146–150

    Article  PubMed  CAS  Google Scholar 

  • 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–S232

    Article  Google Scholar 

  • 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 61:1279–1285

    Article  PubMed  CAS  Google Scholar 

  • 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–S83

    Article  PubMed  CAS  Google Scholar 

  • Michalak A, Butterworth RF (1997) Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. Metab Brain Dis 12:171–182

    Article  PubMed  CAS  Google Scholar 

  • 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 194:163–168

    Article  PubMed  CAS  Google Scholar 

  • 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 59:52–58

    Article  PubMed  CAS  Google Scholar 

  • Montoliu C, Gonzalez-Escamilla G, Atienza M et al (2012) Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy. NeuroImage 61:1165–1175

    Article  PubMed  Google Scholar 

  • 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 88:2450–2458

    PubMed  CAS  Google Scholar 

  • 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 310:1500–1505

    Article  PubMed  CAS  Google Scholar 

  • 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 25:437–441

    Article  PubMed  CAS  Google Scholar 

  • 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 66:282–288

    Article  PubMed  CAS  Google Scholar 

  • 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 145:259–262

    Article  PubMed  CAS  Google Scholar 

  • Norenberg MD, Rao KV, Jayakumar AR (2005) Mechanisms of ammonia-induced astrocyte swelling. Metab Brain Dis 20:303–318

    Article  PubMed  CAS  Google Scholar 

  • Nyberg SL, Cerra FB, Gruetter R (1998) Brain lactate by magnetic resonance spectroscopy during fulminant hepatic failure in the dog. Liver Transp Surg 4:158–165

    Article  CAS  Google Scholar 

  • 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 89:2018–2027

    Article  PubMed  CAS  Google Scholar 

  • Olde Damink SW, Deutz NE, Dejong CH, Soeters PB, Jalan R (2002) Interorgan ammonia metabolism in liver failure. Neurochem Int 41:177–188

    Article  PubMed  CAS  Google Scholar 

  • Oldham MS, vanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL (2010) Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol 42:49–52

    Article  PubMed  Google Scholar 

  • 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 56:109–114

    Article  PubMed  CAS  Google Scholar 

  • 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 55:98–105

    Article  PubMed  CAS  Google Scholar 

  • Patil DH, Westaby D, Mahida YR et al (1987) Comparative modes of action of lactitol and lactulose in the treatment of hepatic encephalopathy. Gut 28:255–259

    Article  PubMed  CAS  Google Scholar 

  • 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 141:104–120

    Article  PubMed  CAS  Google Scholar 

  • 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 16:6123–6127

    Article  PubMed  Google Scholar 

  • Qureshi IA, Rao KV (1997) Sparse-fur (spf) mouse as a model of hyperammonemia: alterations in the neurotransmitter systems. Adv Exp Med Biol 420:143–158

    Article  PubMed  CAS  Google Scholar 

  • Rama Rao KV, Jayakumar AR, Tong X, Curtis KM, Norenberg MD (2010) Brain aquaporin-4 in experimental acute liver failure. J Neuropathol Exp Neurol 69:869–879

    Article  PubMed  CAS  Google Scholar 

  • Rama Rao KV, Jayakumar AR, Norenberg MD (2012) Glutamine in the pathogenesis of acute hepatic encephalopathy. Neurochem Int 61:575–580

    Article  PubMed  CAS  Google Scholar 

  • 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 20:181–192

    Article  PubMed  Google Scholar 

  • Rao VLR (2002) Nitric oxide in hepatic encephalopathy and hyperammonemia. Neurochem Int 41:161–170

    Article  PubMed  CAS  Google Scholar 

  • 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 38:383–394

    Article  PubMed  CAS  Google Scholar 

  • 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 224:83–86

    Article  PubMed  CAS  Google Scholar 

  • 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 184:746–751

    Article  PubMed  CAS  Google Scholar 

  • 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 9:43–51

    Article  PubMed  CAS  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF (1994b) Evidence for cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency. Neurosci Lett 178:63–65

    Article  PubMed  CAS  Google Scholar 

  • 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 274:437–443

    PubMed  CAS  Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF (1996a) Central muscarinic cholinergic M1 and M2 receptor changes in congenital ornithine transcarbamylase deficiency. Pediatr Res 40:25–28

    Article  PubMed  CAS  Google Scholar 

  • 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 215:153–156

    Article  PubMed  CAS  Google Scholar 

  • 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 55:758–771

    Article  PubMed  Google Scholar 

  • 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 58:1016–1022

    Article  PubMed  CAS  Google Scholar 

  • Robinson MB, Heyes MP, Anegawa NJ et al (1992b) Quinolinate in brain and cerebrospinal fluid in rat models of congenital hyperammonemia. Pediatr Res 32:483–488

    Article  PubMed  CAS  Google Scholar 

  • 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 19:150–161

    Article  PubMed  CAS  Google Scholar 

  • 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 55:113–118

    Article  PubMed  CAS  Google Scholar 

  • Rose C (2006) Effect of ammonia on astrocytic glutamate uptake/release mechanisms. J Neurochem 97(Suppl 1):11–15

    Article  PubMed  CAS  Google Scholar 

  • Rose C, Felipo V (2005) Limited capacity for ammonia removal by brain in chronic liver failure: potential role of nitric oxide. Metab Brain Dis 20:275–283

    Article  PubMed  CAS  Google Scholar 

  • 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 13:147–157

    Article  PubMed  CAS  Google Scholar 

  • 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 280:20937–20944

    Article  PubMed  CAS  Google Scholar 

  • Rovira A, Alonso J, Cordoba J (2008) MR imaging findings in hepatic encephalopathy. Am J Neuroradiol 29:1612–1621

    Article  PubMed  CAS  Google Scholar 

  • Salvi S, Santorelli FM, Bertini E et al (2001) Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 57:911–914

    Article  PubMed  CAS  Google Scholar 

  • Scaglia F (2010) New insights in nutritional management and amino acid supplementation in urea cycle disorders. Mol Genet Metab 100(Suppl 1):S72–S76

    Article  PubMed  CAS  Google Scholar 

  • 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 142:113–120

    Google Scholar 

  • 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 109:150–152

    Article  PubMed  Google Scholar 

  • 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–2782S

    PubMed  CAS  Google Scholar 

  • 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 16:739–741

    PubMed  CAS  Google Scholar 

  • 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 20:434–443

    Article  PubMed  CAS  Google Scholar 

  • Shih VE (2007) Alternative-pathway therapy for hyperammonemia. N Engl J Med 356:2321–2322

    Article  PubMed  CAS  Google Scholar 

  • 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 94:2699–2704

    Article  PubMed  CAS  Google Scholar 

  • 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 76:975–989

    Article  PubMed  CAS  Google Scholar 

  • 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 121:125–134

    Article  PubMed  CAS  Google Scholar 

  • Smith W, Kishnani PS, Lee B et al (2005) Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin 21:S9–S17

    Article  PubMed  Google Scholar 

  • 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 68:730–737

    Article  PubMed  CAS  Google Scholar 

  • 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 17:399–413

    Article  PubMed  CAS  Google Scholar 

  • Summar M (2001) Current strategies for the management of neonatal urea cycle disorders. J Pediatr 138:S30–S39

    Article  PubMed  CAS  Google Scholar 

  • Takanashi J, Kurihara A, Tomita M et al (2002) Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency. Neurology 59:210–214

    Article  PubMed  CAS  Google Scholar 

  • 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 24:1184–1187

    PubMed  Google Scholar 

  • Takeoka M, Soman TB, Shih VE, Caviness VS, Krishnamoorthy KS (2001) Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy. Pediatr Neurol 24:193–199

    Article  PubMed  CAS  Google Scholar 

  • 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 131:437–449

    Article  PubMed  CAS  Google Scholar 

  • 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 41:649–656

    Article  PubMed  Google Scholar 

  • 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 62:868–879

    Article  PubMed  CAS  Google Scholar 

  • 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 94:397–402

    Article  PubMed  CAS  Google Scholar 

  • 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):151–159

    Article  PubMed  Google Scholar 

  • Veres G, Gibbs RA, Scherer SE, Caskey CT (1987) The molecular basis of the sparse fur mouse mutation. Science 237:415–417

    Article  PubMed  CAS  Google Scholar 

  • Walker V (2009) Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 11:823–835

    Article  PubMed  CAS  Google Scholar 

  • Wiesinger H (2001) Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol 64:365–391

    Article  PubMed  CAS  Google Scholar 

  • Willard-Mack CL, Koehler RC, Hirata T et al (1996) Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 71:589–599

    Article  PubMed  CAS  Google Scholar 

  • 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 32:410–419

    PubMed  CAS  Google Scholar 

  • 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 52:348–354

    Article  PubMed  Google Scholar 

  • Yamanouchi H, Yokoo H, Yuhara Y et al (2002) An autopsy case of ornithine transcarbamylase deficiency. Brain Dev 24:91–94

    Article  PubMed  Google Scholar 

  • Zanelli SA, Solenski NJ, Rosenthal RE, Fiskum G (2005) Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Ann N Y Acad Sci 1053:153–161

    Article  PubMed  CAS  Google Scholar 

  • 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 58:190–195

    Article  PubMed  CAS  Google Scholar 

  • 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 61:531–535

    Article  PubMed  CAS  Google Scholar 

  • Zwingmann C (2007) The anaplerotic flux and ammonia detoxification in hepatic encephalopathy. Metab Brain Dis 22:235–249

    Article  PubMed  CAS  Google Scholar 

  • 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 37:420–428

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

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.

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  1. Service of Biomedicine, Lausanne University Hospital, Avenue Pierre-Decker 2, CI 02/33, CH-1011, Lausanne, Switzerland

    Olivier Braissant

  2. Pediatric Gastroenterology Unit, Division of Pediatric Specialties, Department of Child and Adolescent, University Hospitals of Geneva (HUG), Geneva, Switzerland

    Valérie A. McLin

  3. Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Cristina Cudalbu

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  1. Olivier Braissant
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Correspondence to Olivier Braissant.

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Communicated by: Pascale de Lonlay

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Braissant, O., McLin, V.A. & Cudalbu, C. Ammonia toxicity to the brain. J Inherit Metab Dis 36, 595–612 (2013). https://doi.org/10.1007/s10545-012-9546-2

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