Alterations in expression of genes coding for key astrocytic proteins in acute liver failure.
ABSTRACT 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.
- SourceAvailable from: Jorge Fischbarg[show abstract] [hide abstract]
ABSTRACT: Water traverses the plasma membranes of some eukaryotic cells faster than can be explained by the water permeability of their lipid bilayers. This has led to a search for a water channel. Our previous work identified glucose transporters as candidates for such a channel. We report here that Xenopus laevis oocytes injected with mRNA encoding the brain/Hep G2, adult skeletal muscle/adipocyte, or liver forms of the glucose transporter exhibit an osmotic water permeability of their plasma membranes larger than that of untreated oocytes. The osmotic water permeability component attributable to glucose transporters increased an average of 4.8-fold in the injected oocytes. These studies provide direct evidence that the facilitative, sodium-independent mammalian glucose transporters serve as membrane water channels.Proceedings of the National Academy of Sciences 05/1990; 87(8):3244-7. · 9.74 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: It has been proposed that alterations of excitatory and inhibitory amino acids play a role in the pathogenesis of hepatic encephalopathy in acute liver failure. To evaluate this possibility, in vivo cerebral microdialysis was used to sample extracellular concentrations of amino acids in the frontal cortex of unanesthetized rats at various times during the progression of encephalopathy resulting from acute liver failure. Liver failure was induced by portacaval anastomosis followed 24 hours later by hepatic artery ligation. Dialysate concentrations of amino acids were measured by high-performance liquid chromatography (HPLC) with fluorescence detection. Deterioration of neurological status was accompanied by two- to four-fold increases in extracellular glutamate, glutamine, and glycine; concentrations of gamma-aminobutyric acid (GABA) and taurine were unchanged. Densities of binding sites for the glutamate (N-methyl-D-aspartate [NMDA]) receptor ligand 3H-MK801, assessed using quantitative receptor autoradiography, however, were unchanged in the frontal cortex of rats at coma stages of ischemic liver failure. Increased extracellular glutamate concentrations were positively correlated with the severity of encephalopathy and with arterial ammonia concentrations. Such changes may result from an ammonia-induced reduction in the capacity for astrocytes to uptake glutamate. Increased extracellular glutamate in brain, together with increases in concentrations of glycine, a positive allosteric modulator of glutamate (NMDA) receptors, are consistent with increased NMDA-related glutamatergic neurotransmission in this model of acute liver failure. Increased extracellular glutamate, therefore, could contribute to the pathogenesis of hepatic encephalopathy and brain edema in acute liver failure.Hepatology 11/1996; 24(4):908-13. · 12.00 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: It has been suggested that alterations of serotonin transport may be implicated in the pathogenesis of the neuropsychiatric symptoms encountered in acute liver failure. In order to address this issue, microdialysate concentrations of serotonin, its precursor L-tryptophan and metabolite 5-hydroxyindoleacetic acid (5-HIAA) as well as brain regional distribution of serotonin transporter ([3H]-citalopram) sites were measured in rats with acute liver failure resulting from hepatic devascularization. A significant loss of [3H]-citalopram sites was observed in dorsal Raphe nucleus, in frontal and frontoparietal cortices as well as in substantia nigra of rats with severe encephalopathy resulting from acute liver failure. In frontal cortex, this loss of transporter binding sites was accompanied by significant increases of L-tryptophan, serotonin and 5-HIAA concentrations in extracellular fluid. Pharmacological manipulation of the brain serotonin system could afford a novel therapeutic approach to the prevention of the neuropsychiatric symptoms characteristic of acute liver failure in humans.Neurochemistry International 03/2001; 38(2):163-68. · 2.66 Impact Factor