Abstract
Hepatic encephalopathy (HE) is a serious complication of liver failure. HE manifests as a series of neuropsychiatric and neuromuscular symptoms including personality changes, sleep abnormalities, asterixis and muscle rigidity progressing through stupor to coma. The pathophysiologic basis of HE remains unclear. There is general agreement that ammonia plays a key role. In recent years, it has been suggested that oxidative/nitrosative stress constitutes part of the pathophysiologic cascade in HE. Direct evidence for oxidative/nitrosative stress in the pathogenesis of HE has been demonstrated in experimental animal models of acute or chronic liver failure. However, evidence from studies in HE patients is limited. This review summarizes this evidence for a role of oxidative/nitrosative stress in relation to ammonia toxicity and to the pathogenesis of HE.
Similar content being viewed by others
Abbreviations
- HE:
-
hepatic encephalopathy
- ALF:
-
acute liver failure
- eNOS:
-
endothelial nitric oxide synthase
- HO-1:
-
heme oxygenase-1
- TAA:
-
thioacetamide
- SOD:
-
superoxide dismutase
- MPT:
-
mitochondrial permeability transition
- PTP:
-
permeability transition pore
- NAC:
-
n-acetylcysteine
- iNOS:
-
inducible nitric oxide synthase
- nNOS:
-
neuronal nitric oxide synthase
- NMDAr:
-
n-methyl-d-aspartic acid receptors
- GS:
-
glutamine synthetase
- MSO:
-
methionine sulfoximine
References
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 49:372–378
Asanuma M, Nishibayashi-Asanuma S, Miyazaki I, Kohno M, Ogawa N (2001) Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals. J Neurochem 76:1895–1904
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
Bemeur C, Ste-Marie L, Desjardins P, Vachon L, Butterworth RF, Hazell AS, Montgomery J (2005) Dehydrascorbic acid normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat. Neurochem Int 46:399–407
Bemeur C, Jiang W, Desjardins P, Butterworth RF (2009) Mild hypothermia attenuates oxidative/nitrosative stress and cytotoxic brain edema in experimental acute liver failure. XXIVth International Symposium on Cerebral Blood Flow, Metabolism and Function & IXth International Conference on Quantification of Brain Function with PET, Chicago, IL, USA
Bemeur C, Vaquero J, Desjardins P, Butterworth RF (2010a) N-Acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis (in press)
Bemeur C, Desjardins P, Butterworth RF (2010b) Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane toxicity in the mouse. Metab Brain Dis (in press)
Bruck R, Aeed H, Shirin H, Matas Z, Zaidel L, Avni Y, Halpern Z (1999) The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure. J Hepatol 31:27–38
Brunk UT (1989) On the origin of lipofuscin; the iron content of residual bodies, and the relation of these organelles to the lysosomal vacuome. A study on cultured human glial cells. Adv Exp Med Biol 266:313–320
Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 2:452–254
Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 17:221–227
Chung C, Gottstein J, Blei AT (2001) Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 34:249–254
Clemmesen JO, Hansen BA, Larsen FS (1997) Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three-year-old woman treated with indomethacin. Hepatology 26:1423–1425
Cordoba J, Crespin J, Gottstein J, Blei AT (1999) Mild hypothermia modifies ammonia- induced brain edema in rats after portacaval anastomosis. Gastroenterology 116:686–693
Desjardins P, Butterworth RF (2002) The “peripheral-type” benzodiazepine (omega 3) receptor in hyperammonemic disorders. Neurochem Int 41:109–114
Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD (1995) Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 65:1704–1711
Görg B, Foster N, Reinehr R, Bidmon HJ, Höngen A, Häussinger D, Schliess F (2003) Benzodiazepine-induced protein tyrosine nitration in rat astrocytes. Hepatology 37:334–342
Görg B, Qvartskhava N, Voss P, Grune T, Häussinger D, Schliess F (2007) Reversible inhibition of mammalian glutamine synthetase by tyrosine nitration. FEBS Lett 581:84–90
Guerrini VH (1994) Effect of antioxidants on ammonia induced CNS-renal pathobiology in sheep. Free Radic Res 21:35–43
Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623
Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R (1991) Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 324:1852–1857
Haseloff RF, Blasig IE, Meffert H, Ebert B (1990) Hydroxyl radical scavenging and antipsoriatic activity of benzoic acid derivatives. Free Radic Biol Med 9:111–115
Hawkins RA, Jessy J, Mans AM, De Joseph MR (1993) Effect of reducing brain glutamine synthesis on metabolic symptoms of hepatic encephalopathy. J Neurochem 60:1000–1006
Hermenegildo C, Marcaida G, Montoliu C, Grisolia S, Minana MD, Felipo V (1996) NMDA receptor antagonists prevent acute ammonia toxicity in mice. Neurochem Res 21:1237–1244
Hermenegildo C, Monfort P, Felipo V (2000) Activation of N-methyl-D-aspartate receptors in rat brain in vivo following acute ammonia intoxication: characterization by in vivo brain microdialysis. Hepatology 31:709–715
Hernández R, Martinez-Lara E, Del Moral ML, Blanco S, Cañuelo A, Siles E, Esteban FJ, Pedrosa JA, Peinado MA (2004) Upregulation of endothelial nitric oxide synthase maintains nitric oxide production in the cerebellum of thioacetamide cirrhotic rats. Neuroscience 126:879–887
Hilgier W, Anderzhanova E, Oja SS, Saransaari P, Albrecht J (2003) Taurine reduces ammonia- and N-methyl-D-aspartate-induced accumulation of cyclic GMP and hydroxyl radicals in microdialysates of the rat striatum. Eur J Pharmacol 468:21–25
Jalan R, Olde Damink SW, Deutz NE, Lee A, Hayes PC (1999) Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 354:1164–1168
Jalan R, Olde Damink SW, Deutz NE, Davies NA, Garden OJ, Machavan KK, Hayes PC, Lee A (2003) Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation 75:2034–2039
Jiang W, Desjardins P, Butterworth RF (2009a) Hypothermia attenuates oxidative/nitrosative stress, encephalopathy and brain edema in acute (ischemic) liver failure. Neurochem Int 55:124–128
Jiang W, Desjardins P, Butterworth RF (2009b) Minocycline attenuates oxidative/nitrosative stress and cerebral complications of acute liver failure in rats. Neurochem Int 55:601–605
Jones AL (1998) Mechanism of action and value of n-acetylcysteine in the treatment of early and late acetaminophen poisoning: a critical review. J Toxicol Clin Toxicol 36:277–285
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 Na+, K(+)-ATPase. J Neurochem 63:2172–2178
Kosenko E, Kaminsky Y, Kaminsky A, Valencia M, Lee L, Hermenegildo C, Felipo V (1997) Superoxide production and antioxidant enzymes in ammonia intoxication in rats. Free Radic Res 27:637–644
Kosenko E, Kaminski Y, Lopata O, Muravyoy N, Felipo V (1999) Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radic Biol Med 26:1369–1374
Kosenko E, Venediktova N, Kaminsky Y, Montoliu C, Felipo V (2003) Sources of oxygen radicals in brain in acute ammonia intoxication in vivo. Brain Res 98:193–200
Kosenko E, Montoliu C, Giordano G, Kaminsky Y, Venediktova N, Buryanov Y, Felipo V (2004) Acute ammonia intoxication induces an NMDA receptor-mediated increase in poly(ADP-ribose) polymerase level and NAD metabolism in nuclei of rat brain cells. J Neurochem 89:1101–1110
Laroux FS, Pavlick KP, Hines IN, Kawachi S, Harada H, Bharwani S, Hoffman JM, Grisham MB (2001) Role of nitric oxide in inflammation. Acta Physiol Scand 173:113–118
Larsen FS, Gottstein J, Blei AT (2001) Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema. J Hepatol 34:548–554
Marcaida G, Felipo V, Hermenegildo C, Manama MD, Grisolia S (1992) Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett 296:67–68
Master S, Gottstein J, Blei AT (1999) Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 30:876–880
Miller TJ, Phelka AD, Tjalkens RB, Dethloff LA, Philbert MA (2003) CI-1010 induced opening of the mitochondrial permeability transition pore precedes oxidative stress and apoptosis in SY5Y neuroblastoma cells. Brain Res 963:43–56
Mousseau DD, Butterworth RF (1994) Current theories on the pathogenesis of hepatic encephalopathy. Proc Soc Exp Biol Med 206:329–344
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
Norenberg MD (1981) The astrocyte in liver disease. Adv Cell Neurobiol 2:303–352
Norenberg MD, Huo Z, Neary JT, Roig-Cantesano A (1997) The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 21:124–133
Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS (2007) New concepts in the mechanism of ammonia-induced astrocyte swelling. Metab Brain Dis 22:219–234
O’Connor JE, Costell M (1990) New roles of carnitine metabolism in ammonia cytotoxicity. Adv Exp Med Biol 272:183–195
Rama Rao KV, Jayakumar AR, Norenberg MD (2003) Ammonia neurotoxicity: role of the mitochondrial permeability transition. Metab Brain Dis 18:113–127
Rama Rao KV, Jayakumar AR, Norenberg MD (2005) Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes. Neurochem Int 47:31–38
Rao VL (2002) Nitric oxide in hepatic encephalopathy and hyperammonemia. Neurochem Int 41:161–170
Rao KV, Norenberg MD (2001) Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis 16:67–78
Rao VL, Audet RM, Butterworth RF (1995) Increased nitric oxide synthase activities and L-[3H]arginine uptake in brain following portacaval anastomosis. J Neurochem 65:677–678
Reddy PV, Murthy CR, Reddanna P (2004) Fulminant hepatic failure induced oxidative stress in nonsynaptic mitochondria of cerebral cortex in rats. Neurosci Lett 368:15–20
Rose C, Michalak A, Pannunzio M, Chatauret N, Rambaldi A, Butterworth RF (2000) Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure. Hepatology 31:872–877
Sathyasaikumar KV, Swapna I, Reddy PV, Murthy ChR, Dutta Gupta A, Senthilkumaran B, Reddanna P (2007) Fulminant hepatic failure in rats induces oxidative stress differentially in cerebral cortex, cerebellum and pons medulla. Neurochem Res 32:517–524
Sawara K, Desjardins P, Chatauret N, Kato A, Suzuki K, Butterworth RF (2009) Alterations in expression of genes coding for proteins of the neurovascular unit in ischemic liver failure. Neurochem Int 55:119–123
Schenker S, Warren KS (1962) Effect of temperature variation on toxicity and metabolism of ammonia in mice. J Lab Clin Med 60:291–301
Schliess F, Görg B, Fischer R, Desjardins P, Bidmon HJ, Herrmann A, Butterworth RF, Zilles K, Häussinger D (2002) Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB J 16:739–741
Schliess F, Görg B, Häussinger D (2006) Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm. Biol Chem 387:1363–1370
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
Suárez I, Bodega G, Rubino M, Felipo V, Fernández B (2005) Neuronal and inducible nitric oxide synthase expression in the rat cerebellum following portacaval anastomosis. Brain Res 1047:205–213
Suárez I, Bodega G, Arilla E, Felipo V, Fernández B (2006) The expression of nNOS, iNOS and nitrotyrosine is increased in the rat cerebral cortex in experimental hepatic encephalopathy. Neuropathol Appl Neurobiol 32:594–604
Sushma S, Dasarathy S, Tandon RK, Jain S, Gupta S, Bhist MS (1992) Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology 16:138–144
Szerb JC, Butterworth RF (1992) Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol 39:135–153
Takahashi H, Koehler RC, Brusilow SW, Traystman RJ (1991) Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 261:H825–H829
Traber P, DalCanto M, Ganger D, Blei AT (1989) Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization. Gastroenterology 96:885–891
Túnez I, Muñoz MC, Medina FJ, Salcedo M, Feijóo M, Montilla P (2007) Comparison of melatonin, vitamin E and L-carnitine in the treatment of neuro- and hepatoxicity induced by thioacetamide. Cell Biochem Funct 25:119–127
Upreti KK, Das M, Khanna SK (1991) Role of antioxidants and scavengers on argemone oil-induced toxicity in rats. Arch Environ Contam Toxicol 20:531–537
Wendon JA, Harrison PM, Keays R, Williams R (1994) Cerebral blood flow and metabolism in fulminant liver failure. Hepatology 19:1407–1413
Zarros A, Theocharis S, Skandali N, Tsakiris S (2008) Effects of fulminant hepatic encephalopathy on the adult rat brain antioxidant status and the activities of acetylcholinesterase, (Na(+), K(+))- and Mg (2+)-ATPase: comparison of the enzymes’ response to in vitro treatment with ammonia. Metab Brain Dis 23:255–264
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bemeur, C., Desjardins, P. & Butterworth, R.F. Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 25, 3–9 (2010). https://doi.org/10.1007/s11011-010-9177-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-010-9177-y