Metabolic Brain Disease

, Volume 24, Issue 1, pp 69–80 | Cite as

Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy

  • Omar Cauli
  • Regina Rodrigo
  • Marta Llansola
  • Carmina Montoliu
  • Pilar Monfort
  • Blanca Piedrafita
  • Nisrin el Mlili
  • Jordi Boix
  • Ana Agustí
  • Vicente FelipoEmail author
Original Paper


Patients with hepatic encephalopathy (HE) may present different neurological alterations including impaired cognitive function and altered motor activity and coordination. HE may lead to coma and death. Many of these neurological alterations are the consequence of altered neurotransmission. Hyperammonemia is a main contributor to the alterations in neurotransmission and in neurological functions in HE. Both glutamatergic and GABAergic neurotransmission are altered in animal models of HE. We review some of these alterations, especially those alterations in glutamatergic neurotransmission responsible for some specific neurological alterations in hyperammonemia and HE: the role 1) of excessive NMDA receptors activation in death induced by acute hyperammonemia; 2) of impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors, in cognitive impairment in chronic HE; 3) of increased extracellular glutamate and activation of metabotropic glutamate receptors in substantia nigra in hypokinesia in chronic HE. The therapeutic implications are discussed. We also review the alterations in the function of the neuronal circuits between basal ganglia-thalamus-cortex modulating motor activity and the role of sequential alterations in glutamatergic and GABAergic neurotransmission in these alterations. HE would be a consequence of altered neuronal communication due to alterations in general neurotransmission involving different neurotransmitter systems in different neurons.


Hepatic encephalopathy Glutamate GABA Hypokinesia Motor function Neuronal circuits Hyperammonemia 



This work was supported by grants from Ministerio de Educación y Ciencia (SAF2005-06089) and from Ministerio de Sanidad (Red G03-155 and FIS PI050253) of Spain and from Consellería de Empresa, Universidad y Ciencia (GV04B-012, GVS05/082, ACOMP06/005; ACOMP/2007/002) and AP005/06 and EVES 034/2007 from Conselleria de Sanitat, Generalitat Valenciana


  1. Ahboucha S, Pomier-Layrargues G, Butterworth RF (2004) Increased brain concentrations of endogenous (non-benzodiazepine) GABAA receptor ligands in human HE. Met Brain Dis 19:241–251CrossRefGoogle Scholar
  2. Ahboucha S, Araqi F, Layrargues GP, Butterworth RF (2005) Differential effects of ammonia on the benzodiazepine modulatory site on the GABAA receptor of human brain. Neurochem Int 47:58–63PubMedCrossRefGoogle Scholar
  3. Ahboucha S, Pomier-Layrargues G, Mamer O, Butterworth RF (2006) Increased levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma. Neurochem Int 49:372–378PubMedCrossRefGoogle Scholar
  4. Aguilar MA, Miñarro J, Felipo V (2000) Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats. Experimental Neurol 161:704–713CrossRefGoogle Scholar
  5. Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 193–194:253–267CrossRefGoogle Scholar
  6. Bernabeu R, Schroder N, Quevedo J, Cammarota M, Izquierdo I, Medina JH (1997) Further evidence for the involvement of a hippocampal cGMP/cGMP-dependent protein kinase cascade in memory consolidation. Neuroreport 8:2221–2224PubMedCrossRefGoogle Scholar
  7. Canales JJ, Elayadi A, Errami M, Llansola M, Cauli O, Felipo V (2003) Chronic hyperammonemia alters motor and neurochemical responses to activation of group I metabotropic glutamate receptors in the nucleus accumbens in rats in vivo. Neurobiol Dis 143:380–390CrossRefGoogle Scholar
  8. Cauli O, Llansola M, Erceg S, Felipo V (2006) Hypolocomotion in rats with chronic liver failure is due to increased glutamate and activation of metabotropic glutamate receptors in substantia nigra. J Hepatol 45:654–661PubMedCrossRefGoogle Scholar
  9. Cauli O, Rodrigo R, Piedrafita B, Boix J Felipo V (2007a) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with porto-caval shunts. Hepatology 46:514–519PubMedCrossRefGoogle Scholar
  10. Cauli O, Mlili N, Rodrigo R, Felipo V (2007b) Hyperammonemia alters the mechanisms by which metabotropic glutamate receptors in nucleus accumbens modulate motor function. J Neurochem 103:38–46PubMedCrossRefGoogle Scholar
  11. Cauli O, Mlili N, Llansola M, Felipo V (2007c) Motor activity is modulated via different neuronal circuits in rats with chronic liver failure than in normal rats. Eur J Neurosci 25:2112–2122PubMedCrossRefGoogle Scholar
  12. Cauli O, López-Larrubia P, Rodrigues TB, Cerdán S, Felipo V (2007d) Magnetic resonance analysis of the effects of acute ammonia intoxication on rat brain. Role of NMDA receptors. J Neurochem 103(4):1334–1343PubMedCrossRefGoogle Scholar
  13. Corbalán R, Chatauret N, Behrends S, Butterworth RF, Felipo V (2002) Region selective alterations of soluble guanylate cyclase content and modulation in brain of cirrhotic patients. Hepatology 36:1155–1162PubMedCrossRefGoogle Scholar
  14. Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V (2005a) Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 41:299–306PubMedCrossRefGoogle Scholar
  15. Erceg S, Monfort P, Hernandez-Viadel M, Llansola M, Montoliu C, Felipo V (2005b) Restoration of learning ability in hyperammonemic rats by increasing extracellular cGMP in brain. Brain Res 1036:115–121PubMedCrossRefGoogle Scholar
  16. Felipo V (2006) Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy. World J Gastroenterol 12:7737–7743PubMedGoogle Scholar
  17. Felipo V (2008a) Hyperammonemia. handbook of neurochemistry and molecular neurobiology, vol. 24, 3rd edn. Kluwer Academic/Plenum, USA, pp 1–27Google Scholar
  18. Felipo V (2008b) Alterations in neurotransmission in hepatic encephalopathy. In: Romero M (ed) Internat hepatology updates hepatic encephalopathy, 1st edn. Permanyer Pub, Barcelona, pp 13–32Google Scholar
  19. Felipo V, Butterworth RF (2002) Neurobiology of ammonia. Prog Neurobiol 67:259–279PubMedCrossRefGoogle Scholar
  20. Felipo V, Minana MD, Grisolía S (1988) Long term ingestion of ammonium increases acetylglutamate and urea levels without affecting the amount of carbamyl phosphate synthase. Eur J Biochem 176:567–571PubMedCrossRefGoogle Scholar
  21. Felipo V, Hermenegildo C, Montoliu C, Llansola M, Miñana MD (1998) Neurotoxicity of ammonia and glutamate: Molecular mechanisms and prevention. NeuroToxicology 19:675–682PubMedGoogle Scholar
  22. Ha JH, Basile AS (1996) Modulation of ligand binding to components of the GABAA receptor complex by ammonia: implications for the pathogenesis of hyperammonemic syndromes. Brain Res 720:35–44PubMedCrossRefGoogle Scholar
  23. Hermenegildo C, Marcaida G, Montoliu C, Grisolia S, Minana MD, Felipo V (1996) NMDA receptor antagonists prevent acute ammonia toxicity in mice. Neurochem Res 21:1237–1244PubMedCrossRefGoogle Scholar
  24. Hermenegildo C, Montoliu C, Llansola M, Muñoz MD, Gaztelu JM, Miñana MD, Felipo V (1998) Chronic hyperammonemia impairs glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J Neurosci 10:3201–3209PubMedCrossRefGoogle Scholar
  25. Hermenegildo C, Monfort P, Felipo V (2000) Activation of NMDA receptors in rat brain in vivo following acute ammonia intoxication. Characterization by in vivo brain microdialysis. Hepatology 31:709–715PubMedCrossRefGoogle Scholar
  26. Itzhak Y, Roig-Cantisano A, Dombro RS, Norenberg MD (1995) Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain. Brain Res 705:345–348PubMedCrossRefGoogle Scholar
  27. Jover R, Company L, Gutierrez A, Lorente M, Zapater P, Poveda MJ et al (2005) Clinical significance of extrapyramidal signs in patients with cirrhosis. J Hepatol 425:659–665CrossRefGoogle Scholar
  28. Kosenko E, Felipo V, Miñana MD, Grau E, Grisolía S (1991) Ammonium ingestion prevents depletion of hepatic energy metabolites induced by acute ammonium intoxication. Arch Biochem Biophys 290:484–488PubMedCrossRefGoogle Scholar
  29. Kosenko E, Kaminsky YG, Felipo V, Miñana MD, Grisolía S (1993) Chronic hyperammonemia prevents changes in brain energy and ammonia metabolites induced by acute ammonium intoxication. Biochim Biophys Acta 1180:321–326PubMedGoogle Scholar
  30. Kosenko E, Kaminsky Y, Grau E, Miñana MD, Marcaida G, Grisolía S, Felipo V (1994) Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and of Na/K ATPase. J Neurochem 63:2172–2178PubMedCrossRefGoogle Scholar
  31. Kosenko E, Kaminski Y, Lopata O, Muravyov N, Kaminsky A, Hermenegildo C, Felipo V (1999) Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Rad Biol Med 26:1369–1374PubMedCrossRefGoogle Scholar
  32. Kosenko E, Kaminsky Y, Stavroskaya IG, Felipo V (2000) Alteration of mitochondrial calcium homeostasis by ammonia-induced activation of NMDA receptors in rat brain in vivo. Brain Res 880:139–146PubMedCrossRefGoogle Scholar
  33. Marcaida G, Felipo V, Hermenegildo C, Minana MD, Grisolia S (1992) Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett 296:67–68PubMedCrossRefGoogle Scholar
  34. Minana MD, Felipo V, Grisolía S (1988) Protective effect of long term ammonium ingestion against acute ammonium intoxication. Biochem Biophys Res Commun 153:979–983PubMedCrossRefGoogle Scholar
  35. Monfort P, Montoliu C, Hermenegildo C, Muñoz MD, Felipo V (2000) Differential effects of acute and chronic hyperammonemia on signal transduction pathways associated to NMDA receptors. Neurochem Int 37:249–253PubMedCrossRefGoogle Scholar
  36. Monfort P, Corbalán R, Martinez L, López-Talavera JC, Córdoba J, Felipo V (2001) Altered content and modulation of soluble guanylate cyclase in the cerebellum of rats with portacaval anastomosis. Neuroscience 104:1119–1125PubMedCrossRefGoogle Scholar
  37. Monfort P, Muñoz MD, ElAyadi A, Kosenko E, Felipo V (2002a) Effects of hyper-ammonemia and liver disease on glutamatergic neurotransmission. Metab Brain Dis 17:237–250PubMedCrossRefGoogle Scholar
  38. Monfort P, Kosenko E, Erceg S, Canales JJ, Felipo V (2002b) Molecular mechanism of acute ammonia toxicity. Role of NMDA receptors. Neurochem Int 41:95–102PubMedCrossRefGoogle Scholar
  39. Myslobodsky MS (1987) gamma-Aminobutyric acid (GABA) and HE: testing the validity of electroencephalographic evidence of the GABA hypothesis. Hepatogastroenterology 34:58–64PubMedGoogle Scholar
  40. Norenberg MD, Itzhak Y, Bender AS (1997) The peripheral benzodiazepine receptor and neurosteroids in HE. Adv Exp Med Biol 420:95–111PubMedGoogle Scholar
  41. Rodrigo R, Erceg S, Rodriguez-Diaz J, Saez-Valero J, Piedrafita B, Suarez I, Felipo V (2007) Glutamate-induced activation of nitric oxide synthase is impaired in cerebral cortex in vivo in rats with chronic liver failure. J Neurochem 102:51–64PubMedCrossRefGoogle Scholar
  42. Romero-Gómez M, Córdoba J, Jover R, delOlmo JA, Ramírez M, Rey R, deMadaria E, Montoliu C, Nuñez D, Flavia M, Compañy L, Rodrigo JM, Felipo V (2007) Value of the Critical Flicker Frequency in patients with Minimal Hepatic Encephalopathy. Hepatology 45(4):879–885PubMedCrossRefGoogle Scholar
  43. Schafer DF, Jones EA (1982) Hepatic encephalopathy and the gamma-aminobutyric acid neurotransmitter system. Lancet 1:18–29PubMedCrossRefGoogle Scholar
  44. Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254PubMedCrossRefGoogle Scholar
  45. Takahashi K, Kameda H, Kataoka M, Sanjou K, Harata N, Akaike N (1993) Ammonia potentiates GABAA response in dissociated rat cortical neurons. Neurosci Lett 151:51–54PubMedCrossRefGoogle Scholar
  46. Timmermann L, Gross J, Kircheis G, Haussinger D, Schnitzler A (2002) Cortical origin of mini-asterixis in hepatic encephalopathy. Neurology 582:295–298Google Scholar
  47. Timmermann L, Gross J, Butz M, Kircheis G, Haussinger D, Schnitzler A (2003) Mini-asterixis in hepatic encephalopathy induced by pathologic thalamo-motor-cortical coupling. Neurology 615:689–692Google Scholar
  48. Vogels BA, Maas MA, Daalhuisen J, Quack G, Chamuleau RA (1997) Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 25:820–827PubMedCrossRefGoogle Scholar
  49. Wang JQ, Mao L (2000) Sustained behavioral stimulation following selective activation of group I metabotropic glutamate receptors in rat striatum. Pharmacol Biochem Behav 653:439–447CrossRefGoogle Scholar
  50. Weissenborn K, Kolbe H (1998) The basal ganglia and portal-systemic encephalopathy. Metab Brain Dis 134:261–272CrossRefGoogle Scholar
  51. Weissenborn K, Bokemeyer M, Krause J, Ennen J, Ahl B (2005) Neurological and neuropsychiatric syndromes associated with liver disease. AIDS 19(Suppl 3):S93–S98PubMedCrossRefGoogle Scholar
  52. Yamada K, Hiramatsu M, Noda Y et al (1996) Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behaviour in mice. Neuroscience 74:365–374PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Omar Cauli
    • 1
  • Regina Rodrigo
    • 1
  • Marta Llansola
    • 1
  • Carmina Montoliu
    • 1
  • Pilar Monfort
    • 1
  • Blanca Piedrafita
    • 1
  • Nisrin el Mlili
    • 1
  • Jordi Boix
    • 1
  • Ana Agustí
    • 1
  • Vicente Felipo
    • 1
  1. 1.Laboratory of NeurobiologyCentro de Investigacion Principe FelipeValenciaSpain

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