Top

Published in:

01-12-2014 | Research Article

Effects of hyperammonemia on brain energy metabolism: controversial findings in vivo and in vitro

Authors: Arne Schousboe, Helle S. Waagepetersen, Renata Leke, Lasse K. Bak

Published in: Metabolic Brain Disease | Issue 4/2014

Abstract

The literature related to the effects of elevated plasma ammonia levels on brain energy metabolism is abundant, but heterogeneous in terms of the conclusions. Thus, some studies claim that ammonia has a direct, inhibitory effect on energy metabolism whereas others find no such correlation. In this review, we discuss both recent and older literature related to this controversial topic. We find that it has been consistently reported that hepatic encephalopathy and concomitant hyperammonemia lead to reduced cerebral oxygen consumption. However, this may not be directly linked to an effect of ammonia but related to the fact that hepatic encephalopathy is always associated with reduced brain activity, a condition clearly characterized by a decreased CMRO₂. Whether this may be related to changes in GABAergic function remains to be elucidated.

Albrecht J, Jones EA (1999) Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J Neurol Sci 170:138–146PubMedCrossRef

Alman RW, Ehrmantraut WR, Fazekas JF, Ticktin HE (1956) Cerebral metabolism in hepatic insufficiency. Am J Med 21:843–849PubMedCrossRef

Basile AS, Gammal SH, Mullen KD, Jones EA, Skolnick P (1988) Differential responsiveness of cerebellar Purkinje neurons to GABA and benzodiazepine receptor ligands in an animal model of hepatic encephalopathy. J Neurosci 8:2414–2421PubMed

Bender AS, Norenberg MD (2000) Effect of ammonia on GABA uptake and release in cultured astrocytes. Neurochem Int 36:389–395PubMedCrossRef

Bessman SP, Bessman AN (1955) The cerebral and peripheral uptake of ammonia in liver disease with an hypothesis for the mechanism of hepatic coma. J Clin Invest 34:622–628PubMedCentralPubMedCrossRef

Butterworth RF (2000) Hepatic encephalopathy: a neuropsychiatric disorder involving multiple neurotransmitter systems. Curr Opin Neurol 13:721–727PubMedCrossRef

Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 17:221–227PubMedCrossRef

Cauli O, Mlili N, Llansola M, Felipo V (2007) Motor activity is modulated via different neuronal circuits in rats with chronic liver failure than in normal rats. Eur J Neurosci 25:2112–2122PubMedCrossRef

Cauli O, Mansouri MT, Agusti A, Felipo V (2009) Hyperammonemia increases GABAergic tone in the cerebellum but decreases it in the rat cortex. Gastroenterology 136:1359–1367PubMedCrossRef

Dadsetan S, Bak LK, Sorensen M, Keiding S, Vilstrup H, Ott P, Leke R, Schousboe A, Waagepetersen HS (2011) Inhibition of glutamine synthesis induces glutamate dehydrogenase-dependent ammonia fixation into alanine in co-cultures of astrocytes and neurons. Neurochem Int 58:482–488CrossRef

Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK, Waagepetersen HS, Schousboe A, Sorensen M (2013) Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake. Hepatology 57:258–265PubMedCrossRef

Drejer J, Schousboe A (1989) Selection of a pure cerebellar granule cell culture by kainate treatment. Neurochem Res 14:751–754PubMedCrossRef

Drejer J, Honore T, Schousboe A (1987) Excitatory amino acid-induced release of ³H-GABA from cultured mouse cerebral cortex interneurons. J Neurosci 7:2910–2916PubMed

Erecinska M, Pastuszko A, Wilson DF, Nelson D (1987) Ammonia-induced release of neurotransmitters from rat brain synaptosomes: differences between the effects on amines and amino acids. J Neurochem 49:1258–1265PubMedCrossRef

Gjedde A, Marrett S, Vafaee M (2002) Oxidative and nonoxidative metabolism of excited neurons and astrocytes. J Cereb Blood Flow Metab 22:1–14PubMedCrossRef

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

Hertz L, Murthy CR, Lai JC, Fitzpatrick SM, Cooper AJ (1987) Some metabolic effects of ammonia on astrocytes and neurons in primary cultures. Neurochem Pathol 6:97–129PubMedCrossRef

Hindfelt B, Siesjo BK (1971) Cerebral effects of acute ammonia intoxication. II. The effect upon energy metabolism. Scand J Clin Lab Invest 28:365–374PubMedCrossRef

Hindfelt B, Plum F, Duffy TE (1977) Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts. J Clin Invest 59:386–396PubMedCentralPubMedCrossRef

Iversen P, Sorensen M, Bak LK, Waagepetersen HS, Vafaee MS, Borghammer P, Mouridsen K, Jensen SB, Vilstrup H, Schousboe A, Ott P, Gjedde A, Keiding S (2009) Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology 136:863–871PubMedCrossRef

Johansen ML, Bak LK, Schousboe A, Iversen P, Sorensen M, Keiding S, Vilstrup H, Gjedde A, Ott P, Waagepetersen HS (2007) The metabolic role of isoleucine in detoxification of ammonia in cultured mouse neurons and astrocytes. Neurochem Int 50:1042–1051PubMedCrossRef

Jones EA (2003) Potential mechanisms of enhanced GABA-mediated inhibitory neurotransmission in liver failure. Neurochem Int 43:509–516PubMedCrossRef

Jones EA, Basile AS (1998) Does ammonia contribute to increased GABA-ergic neurotransmission in liver failure? Metab Brain Dis 13:351–360PubMedCrossRef

Jones EA, Schafer DF, Ferenci P, Pappas SC (1984) The GABA hypothesis of the pathogenesis of hepatic encephalopathy: current status. Yale J Biol Med 57:301–316PubMedCentralPubMed

Kala G, Hertz L (2005) Ammonia effects on pyruvate/lactate production in astrocytes–interaction with glutamate. Neurochem Int 47:4–12PubMedCrossRef

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

Leke R, Bak LK, Schousboe A, Waagepetersen HS (2008) Demonstration of neuron-glia transfer of precursors for gaba biosynthesis in a co-culture system of dissociated mouse cerebral cortex. Neurochem Res 33:2629–2635PubMedCrossRef

Leke R, Bak LK, Anker M, Melo TM, Sorensen M, Keiding S, Vilstrup H, Ott P, Portela LV, Sonnewald U, Schousboe A, Waagepetersen HS (2011a) Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine. Neurotox Res 19:496–510PubMedCrossRef

Leke R, Bak LK, Iversen P, Sorensen M, Keiding S, Vilstrup H, Ott P, Portela LV, Schousboe A, Waagepetersen HS (2011b) Synthesis of neurotransmitter GABA via the neuronal tricarboxylic acid cycle is elevated in rats with liver cirrhosis consistent with a high GABAergic tone in chronic hepatic encephalopathy. J Neurochem 117:824–832PubMedCrossRef

Leke R, de Oliveira DL, Mussulini BH, Pereira MS, Kazlauckas V, Mazzini G, Hartmann CR, Silveira TR, Simonsen M, Bak LK, Waagepetersen HS, Keiding S, Schousboe A, Portela LV (2012) Impairment of the organization of locomotor and exploratory behaviors in bile duct-ligated rats. Plos One 7(5):e36322PubMedCentralPubMedCrossRef

Leke R, Oliveira DL, Forgiarini LF, Escobar TD, Hammes TO, Meyer FS, Keiding S, Silveira TR, Schousboe A (2013) Impairment of short term memory in rats with hepatic encephalopathy due to bile duct ligation. Metab Brain Dis 28:187–192PubMedCrossRef

Li XQ, Dong L, Liu ZH, Luo JY (2005) Expression of gamma-aminobutyric acid A receptor subunits alpha1, beta1, gamma2 mRNA in rats with hepatic encephalopathy. World J Gastroenterol 11:3319–3322PubMed

Lockwood AH, McDonald JM, Reiman RE, Gelbard AS, Laughlin JS, Duffy TE, Plum F (1979) The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J Clin Invest 63:449–460PubMedCentralPubMedCrossRef

McKhann GM, Tower DB (1961) Ammonia toxicity and cerebral oxidative metabolism. Am J Physiol 200:420–424PubMed

Morgan MY, Jakobovits AW, James IM, Sherlock S (1980) Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy. Gastroenterology 78:663–670PubMed

Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310PubMedCrossRef

Oja SS, Saransaari P, Wysmyk U, Albrecht J (1993) Loss of GABAB binding sites in the cerebral cortex of rats with acute hepatic encephalopathy. Brain Res 629:355–357PubMedCrossRef

Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, Arroliga AC, Mullen KD (2003) Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 114:188–193PubMedCrossRef

Ott P, Vilstrup H (2014) Cerebral effects of ammonia in liver disease: current hypotheses. Metab Brain Dis. doi:10.1007/s11011-014-9494-7 PubMed

Ott P, Clemmesen O, Larsen FS (2005) Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis. Neurochem Int 47:13–18PubMedCrossRef

Philips BJ, Armstrong IR, Pollock A, Lee A (1998) Cerebral blood flow and metabolism in patients with chronic liver disease undergoing orthotopic liver transplantation. Hepatology 27:369–376PubMedCrossRef

Posner JB, Plum F (1960) The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy. J Clin Invest 39:1246–1258PubMedCentralPubMedCrossRef

Rao KV, Norenberg MD (2001) Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis 16:67–78PubMedCrossRef

Schousboe A, Bak LK, Waagepetersen HS (2013) Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front Endocrinol 4:102. doi:10.3389/fendo.2013.00102 CrossRef

Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329:364–367PubMedCrossRef

Strauss GI, Moller K, Larsen FS, Kondrup J, Knudsen GM (2003) Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure. Liver Transpl 9:1244–1252PubMedCrossRef

Sunol C, Babot Z, Cristofol R, Sonnewald U, Waagepetersen HS, Schousboe A (2010) A possible role of the non-GAT1 GABA transporters in transfer of GABA from GABAergic to glutamatergic neurons in mouse cerebellar neuronal cultures. Neurochem Res 35:1384–1390PubMedCrossRef

Waagepetersen HS, Sonnewald U, Gegelashvili G, Larsson OM, Schousboe A (2001) Metabolic distinction between vesicular and cytosolic GABA in cultured GABAergic neurons using 13C magnetic resonance spectroscopy. J Neurosci Res 63:347–355PubMedCrossRef

Waniewski RA, Martin DL (1998) Preferential utilization of acetate by astrocytes is attributable to transport. J Neurosci 18:5225–5233PubMed

Wysmyk U, Oja SS, Saransaari P, Albrecht J (1992) Enhanced GABA release in cerebral cortical slices derived from rats with thioacetamide-induced hepatic encephalopathy. Neurochem Res 17:1187–1190PubMedCrossRef

Wysmyk-Cybula U, Dabrowiecki Z, Albrecht J (1986) Changes in the metabolism and binding of GABA in the rat brain in thioacetamide-induced hepatogenic encephalopathy. Biomed Biochim Acta 45:413–419PubMed

Yu AC, Drejer J, Hertz L, Schousboe A (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 41:1484–1487PubMedCrossRef

Yu AC, Schousboe A, Hertz L (1984) Influence of pathological concentrations of ammonia on metabolic fate of ¹⁴C-labeled glutamate in astrocytes in primary cultures. J Neurochem 42:594–597PubMedCrossRef

Zeneroli ML, Iuliano E, Racagni G, Baraldi M (1982) Metabolism and brain uptake of gamma-aminobutyric acid in galactosamine-induced hepatic encephalopathy in rats. J Neurochem 38:1219–1222PubMedCrossRef

Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study. Hepatology 37:420–428PubMedCrossRef

Title: Effects of hyperammonemia on brain energy metabolism: controversial findings in vivo and in vitro
Authors: Arne Schousboe
Helle S. Waagepetersen
Renata Leke
Lasse K. Bak
Publication date: 01-12-2014
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 4/2014
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-014-9513-8

At a glance: The STEP trials

Springer Medicine

Effects of hyperammonemia on brain energy metabolism: controversial findings in vivo and in vitro

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2014

Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases

Mechanisms of hepatic encephalopathy and thiamine deficiency

Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy

Interactions of endoplasmic reticulum and mitochondria Ca2+ stores with capacitative calcium entry

The brain in acute on chronic liver failure

Thiamine triphosphate: a ubiquitous molecule in search of a physiological role