Metabolic Brain Disease

, Volume 24, Issue 1, pp 103–117 | Cite as

Signaling factors in the mechanism of ammonia neurotoxicity

  • M. D. Norenberg
  • K. V. Rama Rao
  • A. R. Jayakumar
Original Paper

Abstract

Mechanisms involved in hepatic encephalopathy (HE) still remain poorly understood. It is generally accepted that ammonia plays a major role in this disorder, and that astrocytes represent the principal target of ammonia neurotoxicity. In recent years, studies from several laboratories have uncovered a number of factors and pathways that appear to be critically involved in the pathogenesis of this disorder. Foremost is oxidative and nitrosative stress (ONS), which is largely initiated by an ammonia-induced increase in intracellular Ca2+. Such increase in Ca2+ activates a number of enzymes that promote the synthesis of reactive oxygen-nitrogen species, including constitutive nitric oxide synthase, NADPH oxidase and phospholipase A2. ONS subsequently induces the mitochondrial permeability transition, and activates mitogen-activated protein kinases and the transcription factor, nuclear factor-kappaB (NF-κB). These factors act to generate additional reactive oxygen-nitrogen species, to phosphorylate various proteins and transcription factors, and to cause mitochondrial dysfunction. This article reviews the role of these factors in the mechanism of HE and ammonia toxicity with a focus on astrocyte swelling and glutamate uptake, which are important consequences of ammonia neurotoxicity. These pathways and factors provide attractive targets for identifying agents potentially useful in the therapy of HE and other hyperammonemic disorders.

Keywords

Astrocytes Ammonia Hepatic encephalopathy Mitochondrial permeability transition Mitogen-activated protein kinases NF-κB Oxidative/nitrosative stress 

References

  1. Abbott NJ, Ronnback L, Hansson E, Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nature Rev Neurosci 7:41–53Google Scholar
  2. Ahboucha S, Pomier-Layrargues GMO, Butterworth RF (2005) Increased brain concentrations of a neuroinhibitory steroid in human hepatic encephalopathy. Ann Neurol 58:169–170PubMedGoogle Scholar
  3. Ahn KS, Sethi G, Aggarwal BB (2007) Nuclear factor-kappa B: from clone to clinic. Curr Molec Med 7:619–637Google Scholar
  4. Albrecht J, Norenberg MD (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44:788–794PubMedGoogle Scholar
  5. Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32:1–14PubMedGoogle Scholar
  6. Anderson CM, Nedergaard M (2003) Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci 26:340–344PubMedGoogle Scholar
  7. Bai G, Rama Rao KV, Murthy ChRK, Panickar KS, Jayakumar AR, Norenberg MD (2001) Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J Neurosci Res 66:981–991PubMedGoogle Scholar
  8. Baldwin AS Jr. (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683PubMedGoogle Scholar
  9. Bassett ML, Mullen KD, Scholz B, Fenstermacher JD, Jones EA (1990) Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy. Gastroenterology 98:747–757PubMedGoogle Scholar
  10. Bender AS, Norenberg MD (1996) Effects of ammonia on L-glutamate uptake in cultured astrocytes. Neurochem Res 21:567–573PubMedGoogle Scholar
  11. Bender AS, Woodbury DM, White HS (1989) β-DL-methylene-aspartate, an inhibitor of aspartate aminotransferase, potently inhibits L-glutamate uptake into astrocytes. Neurochem Res 14:641–646PubMedGoogle Scholar
  12. Bernardi P, Petronilli V (1996) The permeability transition pore as a mitochondrial calcium release channel: a critical reappraisal. J Bioenerg Biomembr 28:131–138PubMedGoogle Scholar
  13. Bernardi P, Krauskopf A, Basso E, Petronilli V, Blalchy-Dyson E, Di Lisa F, Forte MA (2006) The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J 273:2077–2099PubMedGoogle Scholar
  14. Bismuth H, Samuel D, Castaing D, Williams R, Pereira SP (1996) Liver transplantation in Europe for patients with acute liver failure. Semin Liver Dis 16:415–425PubMedGoogle Scholar
  15. Blei AT (2005) The pathophysiology of brain edema in acute liver failure. Neurochem Int 47:71–77PubMedGoogle Scholar
  16. Bowie A, O’Neill LA (2000) Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 59:13–23PubMedGoogle Scholar
  17. Brahma B, Forman RE, Stewart EE, Nicholson C, Rice ME (2000) Ascorbate inhibits edema in brain slices. J Neurochem 74:1263–1270PubMedCrossRefGoogle Scholar
  18. 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 31:27–38PubMedGoogle Scholar
  19. Butterworth RF (2000) The astrocytic ("peripheral-type") benzodiazepine receptor: role in the pathogenesis of portal-systemic encephalopathy. Neurochem Int 36:411–416PubMedGoogle Scholar
  20. Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 17:221–227PubMedGoogle Scholar
  21. Capocaccia L, Angelico M (1991) Fulminant hepatic failure: Clinical features, etiology, epidemiology, and current management. Dig Dis Sci 36:775–779PubMedGoogle Scholar
  22. Chan PH, Yurko M, Fishman RA (1982) Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices. J Neurochem 38:525–531PubMedGoogle Scholar
  23. Chan PH, Longar S, Chen S, Yu AC, Hillered L, Chu L, Imaizumi S, Pereira B, Moore K, Woolworth V, Fishman RA (1989) The role of arachidonic acid and oxygen radical metabolites in the pathogenesis of vasogenic brain edema and astrocytic swelling. Ann N Y Acad Sci 559:237–247PubMedGoogle Scholar
  24. Chen CJ, Liao SL, Kuo JS (2000) Gliotoxic action of glutamate on cultured astrocytes. J Neurochem 75:1557–1565PubMedGoogle Scholar
  25. Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH (2001) MAP kinases. Chem Rev 101:2449–2476PubMedGoogle Scholar
  26. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653PubMedGoogle Scholar
  27. Conn HO, Lieberthal ML (1978) The Hepatic Coma Syndromes and Lactulose. Williams and Wilkins, BaltimoreGoogle Scholar
  28. Czaja MJ, Liu H, Wang Y (2003) Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling. Hepatology 37:1405–1413PubMedGoogle Scholar
  29. De Knegt RJ, Schalm SW, Van Der Rijt CCD, 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 20:19–26PubMedGoogle Scholar
  30. Dixit V, Chang TM (1990) Brain edema and the blood brain barrier in galactosamine-induced fulminant hepatic failore rats. An animal model for evaluation of liver support systems. ASAIO Trans 36:21–27Google Scholar
  31. Drejer J, Larsson OM, Schousboe A (1982) Characterization of L-glutamate uptake into and release from astrocytes and neurons cultured from different brain regions. Exp Brain Res 47:259–269PubMedGoogle Scholar
  32. Duan Y, Gross RA, Sheu SS (2007) Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. J Physiol 585:741–758PubMedGoogle Scholar
  33. Ede RJ, Williams R (1986) Hepatic encephalopathy and cerebral edema. Semin Liver Dis 6:107–118PubMedGoogle Scholar
  34. English JM, Cobb MH (2002) Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 23:40–45PubMedGoogle Scholar
  35. Farooqui AA, Yang HC, Rosenberger TA, Horrocks LA (1997) Phospholipase A2 and its role in brain tissue. J Neurochem 69:889–901PubMedGoogle Scholar
  36. Fitzpatrick SM, Cooper AJ, Hertz L (1988) Effects of ammonia and beta-methylene-DL-aspartate on the oxidation of glucose and pyruvate by neurons and astrocytes in primary culture. J Neurochem 51:1197–1203PubMedGoogle Scholar
  37. Gove CD, Hughes RD, Ede RJ, Williams R (1997) Regional cerebral edema and chloride space in galactosamine-induced liver failure in rats. Hepatology 25:295–301PubMedGoogle Scholar
  38. Görg B, Foster N, Reinehr R, Bidmon HJ, Hongen A, Häussinger D, Schliess F (2003) Benzodiazepine-induced protein tyrosine nitration in rat astrocytes. Hepatology 37:334–342PubMedGoogle Scholar
  39. Guerrini VH (1994) Effect of antioxidants on ammonia induced CNS-renal pathobiology in sheep. Free Radic Res 21:35–43PubMedGoogle Scholar
  40. Haghighat N, McCandless DW (1997) Effect of ammonium chloride on energy metabolism of astrocytes and C6-glioma cells in vitro. Metab Brain Dis 12:287–298PubMedGoogle Scholar
  41. Haghighat N, McCandless DW, Geraminegad P (2000) The effect of ammonium chloride on metabolism of primary neurons and neuroblastoma cells in vitro. Metab Brain Dis 15:151–162PubMedGoogle Scholar
  42. Halestrap AP, Woodfield KY, Connern CP (1997) Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. J Biol Chem 272:3346–3354PubMedGoogle Scholar
  43. Häussinger D, Schliess F (2005) Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy. Neurochem Int 47:64–70PubMedGoogle Scholar
  44. Häussinger D, Görg B, Reinehr R, Schliess F (2005) Protein tyrosine nitration in hyperammonemia and hepatic encephalopathy. Metab Brain Dis 20:285–294PubMedGoogle Scholar
  45. Hazell AS, Butterworth RF (1999) Hepatic encephalopathy: An update of pathophysiologic mechanisms. Proc Soc Exp Biol Med 222:99–112PubMedGoogle Scholar
  46. Hernández-Fonseca K, Cárdenas-Rodríguez N, Pedraza-Chaverri J, Massieu L (2008) Calcium-dependent production of reactive oxygen species is involved in neuronal damage induced during glycolysis inhibition in cultured hippocampal. J Neurosci Res 86:1768–1780PubMedGoogle Scholar
  47. Hoofnagle JH, Carithers RL Jr., Shapiro C, Ascher N (1995) Fulminant hepatic failure: summary of a workshop. Hepatology 21:240–252PubMedGoogle Scholar
  48. Horowitz ME, Schafer DF, Molnar P, Jones EA, Blasberg RG, Patlak CS, Waggoner J, Fenstermacher JD (1983) Increased blood-brain transfer in a rabbit model of acute liver failure. Gastroenterology 84:1003–1011PubMedGoogle Scholar
  49. Israel A (1995) A role for phosphorylation and degradation in the control of NF-kappa B activity. Trends Genet 11:203–205PubMedGoogle Scholar
  50. 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 705:345–348PubMedGoogle Scholar
  51. Jalan R, Pollok A, Shah S, Madhavan K, Simpson KJ (2002) Liver derived pro-inflammatory cytokines may be important in producing intracranial hypertension in acute liver failure. J Hepatol 37:536–538PubMedGoogle Scholar
  52. Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A (2004) Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol 41:613–620PubMedGoogle Scholar
  53. Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253–257PubMedGoogle Scholar
  54. Jayakumar AR, Panickar K, Norenberg MD (2002) Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells. J Neurochem 83:1226–1234PubMedGoogle Scholar
  55. Jayakumar AR, Panickar KS, Murthy ChRK, Norenberg MD (2006) Oxidative stress and MAPK phosphorylation mediate ammonia-induced cell swelling and glutamate uptake inhibition in cultured astrocytes. J Neurosci 26:4774–4784PubMedGoogle Scholar
  56. Jones EA, Weissenborn K (1997) Neurology and the liver. J Neurol Neurosurg Psychiatry 63:279–293PubMedGoogle Scholar
  57. Kato M, Hughes RD, Keays RT, Williams R (1992) Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 15:1060–1066PubMedGoogle Scholar
  58. Keyser DO, Pellmar TC (1994) Synaptic transmission in the hippocampus: critical role for glial cells. Glia 10:237–243PubMedGoogle Scholar
  59. Kimelberg HK, Jalonen T, Walz W (1993) Regulation of the brain microenvironment: transmitters and ions. In: Murphy S (ed) Astrocytes: Pharmacology and Function. Academic, San Diego, pp 193–228Google Scholar
  60. Kleinert H, Pautz A, Linker K, Schwarz PM (2004) Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 500:255–266PubMedGoogle Scholar
  61. Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF (1997) Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett 229:201–203PubMedGoogle Scholar
  62. 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 Rad Res 27:637–644Google Scholar
  63. Kosenko E, Kaminski Y, Lopata O, Muravyov N, Felipo V (1999) Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Rad Biol Med 26:1369–1374PubMedGoogle Scholar
  64. Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15PubMedGoogle Scholar
  65. Kramer RM, Stephenson DT, Roberts EF, Clemens JA (1996) Cytosolic phospholipase A2 (cPLA2) and lipid mediator release in the brain. J Lipid Mediat Cell Signal 14:3–7PubMedGoogle Scholar
  66. Kramer L, Tribl B, Gendo A, Zauner C, Schneider B, Ferenci P, Madl C (2000) Partial pressure of ammonia versus ammonia in hepatic encephalopathy. Hepatology 31:30–34PubMedGoogle Scholar
  67. Krueger KE, Papadopoulos V (1992) Mitochondrial benzodiazepine receptors and the regulation of steroid biosynthesis. Annu Rev Pharmacol Toxicol 32:211–237PubMedGoogle Scholar
  68. Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869PubMedGoogle Scholar
  69. Livingstone AS, Potvin M, Goresky CA, Finlayson MH, Hinchey EJ (1977) Changes in the blood-brain barrier in hepatic coma after hepatectomy in the rat. Gastroenterology 73:697–704PubMedGoogle Scholar
  70. Mans AM, Biebuyck JF, Hawkins RA (1983) Ammonia selectively stimulates neutral amino acid transport across blood-brain barrier. Am J Physiol 245:C74–C77PubMedGoogle Scholar
  71. Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsch T, Macho A, Haeffner A, Hirsch F, Geuskens M, Kroemer G (1996) Mitochondrial permeability transition is a central coordinating event of apoptosis. J Exp Med 184:1155–1160PubMedGoogle Scholar
  72. Martin DL (1992) Synthesis and release of neuroactive substances by glial cells. Glia 5:81–94PubMedGoogle Scholar
  73. Martin H, Voss K, Hufnagl P, Wack R, Wassilew G (1987) Morphometric and densitometric investigations of protoplasmic astrocytes and neurons in human hepatic encephalopathy. Exp Pathol 32:241–250PubMedGoogle Scholar
  74. Martinez AJ (1968) Electron microscopy in human hepatic encephalopathy. Acta Neuropathol (Berl) 11:82–86Google Scholar
  75. Master S, Gottstein J, Blei AT (1999) Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 30:876–880PubMedGoogle Scholar
  76. Matkowskyj KA, Marrero JA, Carroll RE, Danilkovich AV, Green RM, Benya RV (1999) Azoxymethane-induced fulminant hepatic failure in C57BL/6J mice: characterization of a new animal model. Am J Physiol 277:G455–462PubMedGoogle Scholar
  77. McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci USA 89:3170–3174PubMedGoogle Scholar
  78. Mennerick S, Zorumski CF (1994) Glial contributions to excitatory neurotransmission in cultured hippocampal cells. Nature 368:59–62PubMedGoogle Scholar
  79. Moroni F, Lombardi G, Moneti G, Cortesini C (1983) The release and the neosynthesis of glutamic acid are increased in experimental models of hepatic encephalopathy. J Neurochem 40:850–854PubMedGoogle Scholar
  80. Muralikrishna AR, Hatcher JF (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Rad Biol Med 40:376–387Google Scholar
  81. Murthy CR, Hertz L (1988) Pyruvate decarboxylation in astrocytes and in neurons in primary cultures in the presence and the absence of ammonia. Neurochem Res 13:57–61PubMedGoogle Scholar
  82. Murthy ChRK, Rama Rao KV, Bai G, Norenberg MD (2001) Ammonia induced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 66:282–288PubMedGoogle Scholar
  83. Nedergaard M (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263:1768–1771PubMedGoogle Scholar
  84. Nguyen JH, Yamamoto S, Steers J, Sevlever D, Lin W, Shimojima N, Castanedes-Casey M, Genco P, Golde T, Richelson E, Dickson D, McKinney M, Eckman CB (2006) Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. J Hepatol 44:1105–1114PubMedGoogle Scholar
  85. Norenberg MD (1977) A light and electron microscopic study of experimental portal-systemic (ammonia) encephalopathy. Progression and reversal of the disorder. Lab Invest 36:618–627Google Scholar
  86. Norenberg MD (1981) The astrocyte in liver disease. In: Fedoroff S, Hertz L (eds) Advances in Cellular Neurobiology, Vol. 2. Academic Press, New York, pp 303–352Google Scholar
  87. Norenberg MD (1987) The role of astrocytes in hepatic encephalopathy. Neurochem Pathol 6:13–33PubMedGoogle Scholar
  88. Norenberg MD (1998) Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis 13:319–335PubMedGoogle Scholar
  89. Norenberg MD (2001) Astrocytes and ammonia in hepatic encephalopathy. In: de Vellis J (ed) Astrocytes in the Aging Brain. Humana Press, Totowa, NJ, pp 477–496Google Scholar
  90. Norenberg MD, Rao KV (2007) The mitochondrial permeability transition in neurologic disease. Neurochem Int 50:983–997PubMedGoogle Scholar
  91. Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310PubMedGoogle Scholar
  92. Norenberg MD, Huo ZF, Neary JT, Roig-Cantesano A (1997) The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: Relation to energy metabolism and glutamatergic neurotransmission. Glia 21:124–133PubMedGoogle Scholar
  93. Norenberg MD, Rama Rao KV, Jayakumar AR (2003) The mitochondrial permeability transition in ammonia neurotoxicity. In: Jones EA, Meijer AF, Chamuleau RA (eds) Hepatic Encephalopathy and Nitrogen Metabolism. Kluwer, Dordtrecht, pp 267–285Google Scholar
  94. Norenberg MD, Rama Rao KV, Jayakumar AR (2004a) Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr 36:303–307PubMedGoogle Scholar
  95. Norenberg MD, Jayakumar AR, Rama Rao KV (2004b) Oxidative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 19:313–329PubMedGoogle Scholar
  96. Norenberg MD, Rama Rao KV, Jayakumar AR (2005) Mechanisms of ammonia-induced astrocyte swelling. Metab Brain Dis 20:303–318PubMedGoogle Scholar
  97. Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS (2006) The peripheral benzodiazepine receptor and neurosteroids in the pathogenesis of hepatic encephalopathy and ammonia neurotoxicity. In: Haussinger D (ed) Hepatic Encephalopathy and Nitrogen Metabolism. Kluver, Dordtrecht, pp 143–159Google Scholar
  98. Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS (2007) New concepts in the mechanism of ammonia-induced astrocyte swelling. Metab Brain Dis 22:219–234PubMedGoogle Scholar
  99. O’Beirne JP, Chouhan M, Hughes RD (2006) The role of infection and inflammation in the pathogenesis of hepatic encephalopathy and cerebral edema in acute liver failure. Nature Clin Pract Gastroenterol Hepatol 3:118–119Google Scholar
  100. 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 114:188–193PubMedGoogle Scholar
  101. Panickar KS, Jayakumar AR, Rama Rao KV, Norenberg MD (2007) Downregulation of the 18-kDa translocator protein: effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes. Glia 55:1720–1727PubMedGoogle Scholar
  102. Papadopoulos V, Brown AS (1995) Role of the peripheral-type benzodiazepine receptor and the polypeptide diazepam binding inhibitor in steroidogenesis. J Steroid Biochem Mol Biol 53:103–110PubMedGoogle Scholar
  103. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (2006) Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27:402–409PubMedGoogle Scholar
  104. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747PubMedGoogle Scholar
  105. Pearson G, Robinson F, Beers GT, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183PubMedGoogle Scholar
  106. Piani D, Frei K, Pfister H-W, Fontana A (1993) Glutamate uptake by astrocytes is inhibited by reactive oxygen intermediates but not by other macrophage-derived molecules including cytokines, leukotrienes or platelet-activating factor. J Neuroimmunol 48:99–104PubMedGoogle Scholar
  107. Pichili VBR, Rama Rao KV, Jayakumar AR, Norenberg MD (2007) Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity. Glia 55:801–809PubMedGoogle Scholar
  108. Qureshi K, Rao KVR, Qureshi IA (1998) Differential inhibition by hyperammonemia of the electron transport chain enzymes in synaptosomes and non-synaptic mitochondria in ornithine transcarbamplase-deficient spf-mice: restoration by acetyl-L-carnitine. Neurochem Res 23:855–861PubMedGoogle Scholar
  109. Rama Rao KV, Norenberg MD (2001) Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis 16:67–78Google Scholar
  110. Rama Rao KV, Norenberg MD (2004) Manganese induces the mitochondrial permeability transition in cultured astrocytes. J Biol Chem 279:32333–32338Google Scholar
  111. Rama Rao KV, Chen M, Simard J, Norenberg MD (2003) Suppression of ammonia-induced astrocyte swelling by cyclosporin A. J Neurosci Res 74:891–897PubMedGoogle Scholar
  112. Rama Rao KV, Jayakumar AR, Norenberg MD (2005) Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes. Neurochem Int 47:31–38PubMedGoogle Scholar
  113. Ransom BR, Sontheimer H (1992) The neurophysiology of glial cells. J Clin Neurophysiol 9:224–251PubMedGoogle Scholar
  114. Rao VLR, Murthy ChRK, Butterworth RF (1992) Glutamatergic synaptic dysfunction in hyperammonemic syndromes. Metab Brain Dis 7:1–20PubMedGoogle Scholar
  115. Rao KVR, 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 224:83–86PubMedGoogle Scholar
  116. Reinehr R, Görg B, Becker S, Qvartskhava N, Bidmon HJ, Selbach O, Haas HL, Schliess F, Häussinger D (2007) Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices. Glia 55:758–771PubMedGoogle Scholar
  117. Risau W, Wolburg H (1990) Development of the blood-brain barrier. Trends Neurosci 13:174–178PubMedGoogle Scholar
  118. 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 280:20937–20944PubMedGoogle Scholar
  119. Schliess F, Görg B, Häussinger D (2006) Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm. Biol Chem 387:1363–1370PubMedGoogle Scholar
  120. 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 16:739–741PubMedGoogle Scholar
  121. Schousboe A (1981) Transport and metabolism of glutamate and GABA in neurons and glial cells. Int Rev Neurobiol 22:1–45PubMedGoogle Scholar
  122. Scorrano L, Penzo D, Petronilli V V, Pagano F, Bernardi P (2000) Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for TNF-alpha apoptotic signaling. J Biol Chem 276:12035–12040Google Scholar
  123. Sharma P (1996) Effect of ascorbic acid on hyperoxic rat astrocytes. Neuroscience 72:391–397PubMedGoogle Scholar
  124. Sheline CT, Wei L (2006) Free radical-mediated neurotoxicity may be caused by inhibition of mitochondrial dehydrogenases in vitro and in vivo. Neuroscience 140:235–246PubMedGoogle Scholar
  125. Sinke AP, Jayakumar AR, Panickar KS, Moriyama M, Reddy PV, Norenberg MD (2008) NFκB in the mechanism of ammonia-induced astrocyte swelling in culture. J Neurochem 106:2302–2311PubMedGoogle Scholar
  126. 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 68:730–737PubMedGoogle Scholar
  127. Stancovski I, Baltimore D (1997) NF-kappaB activation: the I kappaB kinase revealed? Cell 91:299–302PubMedGoogle Scholar
  128. Staub F, Winkler A, Peters J, Kempski O, Kachel V, Baethmann A (1994) Swelling, acidosis, and irreversible damage of glial cells from exposure to arachidonic acid in vitro. J Cereb Blood Flow Metab 14:1030–1039PubMedGoogle Scholar
  129. Suzuki YJ, Forman HJ, Sevanian A (1997) Oxidants as stimulators of signal transduction. Free Rad Biol Med 22:269–285PubMedGoogle Scholar
  130. Swain MS, Blei AT, Butterworth RF, Kraig RP (1991) Intracellular pH rises and astrocytes swell after portacaval anastomosis in rats. Am J Physiol Regul Integr Comp Physiol 261:R1491–R1496Google Scholar
  131. Szerb JC, Butterworth RF (1992) Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol 39:135–153PubMedGoogle Scholar
  132. Traber PG, Dal Canto MC, Ganger D, Blei AT (1987) Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure: ultrastructure and integrity of the blood-brain barrier. Hepatology 7:1272–1277PubMedGoogle Scholar
  133. Ullian EM, Christopherson KS, Barres BA (2004) Role for glia in synaptogenesis. Glia 47:209–216PubMedGoogle Scholar
  134. Vaquero J, Chung C, Blei AT (2003) Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy. Ann Hepatol 2:12–22Google Scholar
  135. Verma IM, Stevenson J (1997) IkappaB kinase: beginning, not the end. Proc Natl Acad Sci USA 94:11758–11760PubMedGoogle Scholar
  136. Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J Neurosci 14:2924–2932PubMedGoogle Scholar
  137. Voorhies TM, Ehrlich ME, Duffy TE, Petito CK, Plum F (1983) Acute hyperammonemia in the young primate. Physiologic and neuropathological correlates. Pediatr Res 17:970–975Google Scholar
  138. Votyakova TV, Reynolds IJ (2001) ΔΨm-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem 79:266–277PubMedGoogle Scholar
  139. Walz W (1989) Role of glial cells in the regulation of the brain ion microenvironment. Prog Neurobiol 33:309–333PubMedGoogle Scholar
  140. Warren KS, Schenker S (1964) Effect of an inhibition of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J Lab Clin Med 64:442–449PubMedGoogle Scholar
  141. Widmer R, Kaiser B, Engels M, Jung T, Grune T (2007) Hyperammonemia causes protein oxidation and enhanced proteasomal activity in response to mitochondria-mediated oxidative stress in rat primary astrocytes. Arch Biochem Biophys 464:1–11PubMedGoogle Scholar
  142. Winkler AS, Baethmann A, Peters J, Kempski O, Staub F (2000) Mechanisms of arachidonic acid induced glial swelling. Brain Res Mol Brain Res 76:419–423PubMedGoogle Scholar
  143. Wright G, Davies NA, Shawcross DL, Hodges SJ, Zwingmann C, Brooks HF, Mani AR, Harry D, Stadlbauer V, Zou Z, Williams R, Davies C, Moore KP, Jalan R (2007) Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology 45:1517–1526PubMedGoogle Scholar
  144. Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269:4705–4708PubMedGoogle Scholar
  145. Zhou BG, Norenberg MD (1999) Ammonia downregulates GLAST mRNA glutamate transporter in rat astrocyte cultures. Neurosci Lett 276:145–148PubMedGoogle Scholar
  146. Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241:139–176PubMedGoogle Scholar
  147. Zorov DB, Juhaszova M, Sollott SJ (2006) Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta 1757:509–517PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • M. D. Norenberg
    • 1
    • 2
    • 3
  • K. V. Rama Rao
    • 1
  • A. R. Jayakumar
    • 1
  1. 1.Department of Pathology (D-33)University of Miami School of MedicineMiamiUSA
  2. 2.Biochemistry & Molecular BiologyUniversity of Miami School of MedicineMiamiUSA
  3. 3.Veterans Affairs Medical CenterMiamiUSA

Personalised recommendations