Metabolic Brain Disease

, Volume 25, Issue 1, pp 17–21

Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure

  • Anne Chastre
  • Wenlei Jiang
  • Paul Desjardins
  • Roger F. Butterworth
Original Paper
  • 282 Downloads

Abstract

There is evidence to suggest that, in acute liver failure (ALF), brain ammonia and proinflammatory cytokines may act synergistically to cause brain edema and its complications (intracranial hypertension, brain herniation). However, the molecular mechanisms involved remain to be established. In order to address this issue, semi-quantitative RT-PCR was used to measure the expression of genes coding for astrocytic proteins with an established role in cell volume regulation in cerebral cortical astrocytes exposed to toxic agents previously identified in experimental and clinical ALF. Such agents include ammonia, the proinflammatory cytokine interleukin-1beta (IL-1β) and combinations of the two. Exposure of cultured astrocytes to recombinant IL-1β (but not ammonia) resulted in increased expression of aquaporin-4 (AQP-4). Both ammonia and proinflammatory mediators led to decreased expression of glial fibrillary acidic protein (GFAP), a cytoskeletal protein, but these effects were not additive. On the other hand, heme oxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) expression were significantly increased by exposure to both ammonia and proinflammatory mediators and although modest, these effects were additive suggestive of a synergistic mechanism. These findings suggest that worsening of brain edema and its complications in ALF due to proinflammatory mechanisms may result from exacerbation of oxidative stress-related mechanisms rather than upregulation of AQP-4 or decreases in expression of the astrocytic structural protein GFAP.

Keywords

Ammonia Acute liver failure Neuroinflammation Proinflammatory cytokines Brain edema Hepatic encephalopathy Oxidative stress 

References

  1. Bélanger M, Desjardins P, Chatauret N, Butterworth RF (2002) Loss of expression of glial fibrillary acidic protein in acute hyperammonemia. Neurochem Int 41:155–160CrossRefPubMedGoogle Scholar
  2. Blei AT (2004) Infection, inflammation and hepatic encephalopathy, synergism redefined. J Hepatol 40:327–330CrossRefPubMedGoogle Scholar
  3. Chan H, Butterworth RF, Hazell AS (2004) Primary cultures of rat astrocytes respond to thiamine deficiency-induced swelling by downregulating aquaporin-4 levels. Neurosci Lett 366:231–234CrossRefPubMedGoogle Scholar
  4. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653CrossRefPubMedGoogle Scholar
  5. Eefsen M, Bisgaard C, Jelnes P, Scmidt LE, Vainer B, Larsen FS (2009) The role of aquaporin-4 and -1 in development of brain edema in experimental liver failure. Hepatology 50:398A [abstract]Google Scholar
  6. 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 41:613–620CrossRefPubMedGoogle Scholar
  7. Jiang W, Desjardins P, Butterworth RF (2009a) Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab 29:944–952CrossRefPubMedGoogle Scholar
  8. Jiang W, Desjardins P, Butterworth RF (2009b) Minocycline attenuates oxidative/nitrosative stress and cerebral complications of acute liver failure in rats. Neurochem Int 55:601–605CrossRefPubMedGoogle Scholar
  9. 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 26:1369–1374CrossRefPubMedGoogle Scholar
  10. Mans AM, Saunders SJ, Kirsch RE, Biebuyck JF (1979) Correlation of plasma and brain amino acid and putative neurotransmitter alterations during acute hepatic coma in the rat. J Neurochem 32:285–292CrossRefPubMedGoogle Scholar
  11. Margulies JE, Thompson RC, Demetriou AA (1999) Aquaporin-4 water channel is up-regulated in the brain in fulminant hepatic failure. Hepatology 30:395a [abstract]CrossRefGoogle Scholar
  12. Murthy CRK, Bai G, Dombro RS, Norenberg MD (2000) Ammonia-induced swelling in primary cultures of rat astrocytes: role of free radicals. Soc Neurosci Abstr 26:1893 [abstract]Google Scholar
  13. Nagaki M, Iwai H, Naiki T, Ohnishi H, Muto Y, Moriwaki H (2000) High levels of serum interleukin-10 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis. J Infect Dis 182:1103–1108CrossRefPubMedGoogle Scholar
  14. Neary JT, Whittemore SR, Zhu Q, Norenberg MD (1994) Destabilization of glial fibrillary acidic protein mRNA in astrocytes by ammonia and protection by extracellular ATP. J Neurochem 63:2021–2027PubMedCrossRefGoogle Scholar
  15. Norenberg MD, Neary JT, Norenberg LO, McCarthy M (1990) Ammonia induced decrease in glial fibrillary acidic protein in cultured astrocytes. J Neuropathol Exp Neurol 49:399–405CrossRefPubMedGoogle Scholar
  16. Norenberg MD, Rao KV, Jayakumar AR (2005) Mechanisms of ammonia-induced astrocyte swelling. Metab Brain Dis 20:303–318CrossRefPubMedGoogle Scholar
  17. O’Connor JE, Costell M (1990) New roles of carnitine metabolism in ammonia cytotoxicity. Adv Exp Med Biol 272:183–195PubMedGoogle Scholar
  18. Rama Rao KV, Norenberg MD (2007) Aquaporin-4 in hepatic encephalopathy. Metab Brain Dis 22:265–275CrossRefPubMedGoogle Scholar
  19. Rama Rao KV, Chen M, Simard JM, Norenberg MD (2003) Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. NeuroReport 14:2379–2382CrossRefPubMedGoogle Scholar
  20. Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R (2000) The systemic inflammatory response syndrome in acute liver failure. Hepatology 32:734–739CrossRefPubMedGoogle Scholar
  21. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386PubMedGoogle Scholar
  22. 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
  23. Swain M, Butterworth RF, Blei AT (1992a) Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats. Hepatology 15:449–453CrossRefPubMedGoogle Scholar
  24. Swain M, Bergeron M, Audet R, Blei AT, Butterworth RF (1992b) Monitoring of neurotransmitter amino acids by means an indwelling cisterna magna catheter: a comparison of two rodent models of fulminant hepatic failure. Hepatology 16:1028–1035CrossRefPubMedGoogle Scholar
  25. Vaquero J, Chung C, Blei AT (2003) Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy. Ann Hepatol 2:12–22PubMedGoogle Scholar
  26. Wright G, Shawcross D, Olde Damink SW, Jalan R (2007) Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 22:375–388CrossRefPubMedGoogle Scholar
  27. Zielińska M, Law RO, Albrecht J (2003) Excitotoxic mechanism of cell swelling in rat cerebral cortical slices treated acutely with ammonia. Neurochem Int 43:299–303CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Anne Chastre
    • 1
  • Wenlei Jiang
    • 1
  • Paul Desjardins
    • 1
  • Roger F. Butterworth
    • 2
  1. 1.Neuroscience Research Unit, St-Luc Hospital (CHUM)University of MontrealMontrealCanada
  2. 2.Neuroscience Research Unit, St-Luc Hospital (CHUM)University of MontrealMontrealCanada

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