Alterations in expression of genes coding for key astrocytic proteins in acute liver failure

Neuroscience Research Unit, Hôpital Saint-Luc du CHUM (University of Montreal), 1058 St-Denis Street, Montreal, Quebec H2X 3J4, Canada.
Journal of Neuroscience Research (Impact Factor: 2.59). 01/2002; 66(5):967-71. DOI: 10.1002/jnr.10045
Source: PubMed


Cerebral edema and hepatic encephalopathy are major complications of acute liver failure. Brain herniation caused by increased intracranial pressure as a result of cell swelling is the major cause of death in this condition. Evidence available currently suggests that the rapid accumulation of ammonia by the brain is the major cause of the central nervous system complications of acute liver failure. Increased brain ammonia may cause cell swelling via the osmotic effects of an increase in astrocytic glutamine concentrations or by inhibition of glutamate removal from brain extracellular space. Acute liver failure results in altered expression of several genes in brain, some of which code for important proteins involved in CNS function such as the glucose (GLUT-1) and glutamate (GLT-1) transporters, the astrocytic structural protein glial fibrillary acidic protein (GFAP) the "peripheral-type" benzodiazepine receptor (PTBR) and the water channel protein, aquaporin IV. Loss of expression of GLT-1 results in increased extracellular brain glutamate in acute liver failure. Experimental acute liver failure also results in post-translational modifications of the serotonin and noradrenaline transporters resulting in increased extracellular concentrations of these monoamines. Therapeutic measures currently used to prevent and treat brain edema and encephalopathy in patients with acute liver failure include mild hypothermia and the ammonia-lowering agent L-ornithine-L-aspartate.

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    • "The transport across the endothelial cell includes passive diffusion for lipid soluble and non-polar molecules; solute carriers including glucose, amino acids, and nucleosides; and receptor and adsorptive mediated transcytosis (Abbott et al., 2010). Glutamate and glucose transporters are significantly altered in brains of ALF animals (Belanger et al., 2006; Desjardins et al., 2001; Knecht et al., 1997). Increased vesicles have been observed in brain endothelial cells of animals and patients with ALF (Gove et al., 1997; Kato et al., 1992; Traber et al., 1987). "
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    ABSTRACT: Brain edema remains a challenging obstacle in the management of acute liver failure (ALF). Cytotoxic mechanisms associated with brain edema have been well recognized, but evidence for vasogenic mechanisms in the pathogenesis of brain edema in ALF has been lacking. Recent reports have not only shown a role of matrix metalloproteinase-9 in the pathogenesis of brain edema in experimental ALF but have also found significant alterations in the tight junction elements including occludin and claudin-5, suggesting a vasogenic injury in the blood-brain barrier (BBB) integrity. This article reviews and explores the role of the paracellular tight junction proteins in the increased selective BBB permeability that leads to brain edema in ALF.
    Neurochemistry International 11/2011; 60(7):676-83. DOI:10.1016/j.neuint.2011.10.012 · 3.09 Impact Factor
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    • "To date, there are limited data on changes in the composition of brain endothelial cells in FHF. Certain astrocyte genes have been shown to be significantly altered in FHF [10]. Both endothelial and astrocytic glucose transporter proteins are selectively altered in brains of FHF animals [11]. "
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    ABSTRACT: Brain edema secondary to increased blood-brain barrier (BBB) permeability is a lethal complication in fulminant hepatic failure (FHF). Intact tight junctions (TJ) between brain capillary endothelial cells are critical for normal BBB function. However, the role of TJ in FHF has not been explored. We hypothesized that alterations in the composition of TJ proteins would result in increased BBB permeability in FHF. In this study, FHF was induced in C57BL/6J mice by using azoxymethane. BBB permeability was assessed with sodium fluorescein. Expression of TJ proteins was determined by Western blot, and their cellular distribution was examined using immunofluorescent microscopy. Comatose FHF mice had significant cerebral sodium fluorescein extravasation compared with control and precoma FHF mice, indicating increased BBB permeability. Western blot analysis showed a significant decrease in zonula occludens (ZO)-2 expression starting in the precoma stage. Immunofluorescent microscopy showed a significantly altered distribution pattern of ZO-2 in isolated microvessels from precoma FHF mice. These changes were more prominent in comatose FHF animals. Significant alterations in ZO-2 expression and distribution in the tight junctions preceded the increased BBB permeability in FHF mice. These results suggest that ZO-2 may play an important role in the pathogenesis of brain edema in FHF.
    Journal of Investigative Surgery 05/2008; 21(3):101-8. DOI:10.1080/08941930802043565 · 1.16 Impact Factor
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    • "Acute hyperammonemia causes astrocytic swelling leading to intracranial hypertension which can potentially cause brain herniation and death in severe cases. A growing number of studies have demonstrated that hyperammonemia causes changes in cerebral and, in particular, astrocytic gene expression (see Desjardins et al., 2001 for review). In contrast to the wealth of information available on astrocytes, little is known about the effects of ammonia on the function and gene expression of brain capillary endothelial cells constituting the BBB. "
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    ABSTRACT: Ammonia is a key neurotoxin involved in the neurological complications of acute liver failure. The present study was undertaken to study the effects of exposure to pathophysiologically relevant concentrations of ammonium chloride on cultured brain capillary endothelial cells in order to identify mechanisms by which ammonia may alter blood-brain barrier function. Conditionally immortalized mouse brain capillary endothelial cells (TM-BBB) were used as an in vitro model of the blood-brain barrier. Gene expression of a series of blood-brain barrier transporters and tight junction proteins was assessed by quantitative real time PCR analysis. Exposure to ammonia (5mM for 72h) resulted in significant increases in mRNA levels of taurine transporter (TAUT; 2.0-fold increase) as well as creatine transporter (CRT; 1.9-fold increase) whereas claudin-12 mRNA expression was significantly reduced to 67.7% of control levels. Furthermore, [(3)H]taurine and [(14)C]creatine uptake were concomitantly increased following exposure to ammonia, suggesting that up-regulation of both TAUT and CRT under hyperammonemic conditions results in an increased function of these two transporters in TM-BBB cells. TAUT and CRT are respectively involved in osmoregulation and energy buffering in the brain, two systems that are thought to be affected in acute liver failure. Furthermore, claudin-12 down-regulation suggests that hyperammonemia may also affect tight junction integrity. Our results provide evidence that ammonia can alter brain capillary endothelial cell gene expression and transporter function. These findings may be relevant to pathological situations involving hyperammonemia, such as liver disease.
    Neurochemistry International 02/2007; 50(1):95-101. DOI:10.1016/j.neuint.2006.07.005 · 3.09 Impact Factor
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