Selective Loss of Binding Sites for the Glutamate Receptor Ligands [3H]Kainate and (S)–[3H]5–Fluorowillardiine in the Brains of Rats With Acute Liver Failure

Michalak, Adrianna; Butterworth, Roger F.

doi:10.1002/hep.510250323

Cited by 44 publications

(16 citation statements)

References 25 publications

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“…Similar results were obtained with experimental animals in chronic encephalopathy models (Baker et al 1990;Rossle et al 1990). Such animals at coma stages of encephalopathy showed unaltered [ 3 H]MK-801 binding to the NMDA receptor (similar to our findings), whereas a significant loss-up to 60%-of [ 3 H]kainate binding in hippocampus and cerebellum and of [ 3 H]5-fluorowillardiine binding to the AMPA receptor in hippocampus when compared to control animals were found (Michalak and Butterworth 1997). All these findings stand in sharp contrast to those in tautÀ/À mice in which [ 3 H]kainate binding was increased in parts of the hippocampus and in the cerebellum.…”

Section: Discussionsupporting

confidence: 77%

“…B bound, F free. Note that scaling for the two genotypes in a given region for a given receptor is always identical, but not for the different regions, nor for the different receptors correlation between brain taurine levels and [ 3 H]kainate binding, since we found that decreased taurine levels correlated with increased [ 3 H]kainate binding, and Michalak and Butterworth (1997) reported decreased [ 3 H]kainate binding if taurine levels were increased.…”

Section: Discussionmentioning

confidence: 68%

“…Under pathological conditions such as hepatic encephalopathy, unaltered GABA A -and NMDAreceptor binding is accompanied by a downregulation of kainate and AMPA receptor binding (Butterworth et al 1988;Maddison et al 1991;Michalak and Butterworth 1997). Since hepatic encephalopathy is associated with astrocyte swelling, volume regulation by taurine efflux and loss of taurine from cells, we address the question of whether taurine deficiency in the tautÀ/À animal is responsible for the changes in receptor density in a similar manner to that seen in cases of human encephalopathy.…”

Section: Introductionmentioning

confidence: 99%

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Taurine-transporter gene knockout-induced changes in GABAA, kainate and AMPA but not NMDA receptor binding in mouse brain

et al. 2005

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The aim of this study was to determine whether the knockout of the taurine-transporter gene in the mouse affects the densities of GABA(A), kainate, AMPA and NMDA receptors in the brain. The caudate-putamen, the hippocampus and its subregions, and the cerebellum of six homozygous taurine-transporter gene knockout mice and six wild-type (WT) animals were examined by means of quantitative receptor autoradiography. Saturation studies were carried out for all four receptor types in order to find possible intergroup differences in Bmax and K(D) values. Taurine-transporter gene knockout animals showed significantly higher GABA(A) receptor densities in the molecular layer of the hippocampal dentate gyrus and in the cerebellum than did WT animals. The densities of kainate receptors were significantly higher in the caudate-putamen, the CA1 and hilus regions of the hippocampus and in the cerebellum of knockout animals. The caudate-putamen and cerebellum of these mice also contained significantly higher AMPA receptor densities. However, there were no significant differences between knockout and WT animals concerning the densities of NMDA receptors. Reduced brain taurine levels are associated with increased GABA(A), kainate and AMPA receptor densities in some of the regions we examined.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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Taurine-transporter gene knockout-induced changes in GABAA, kainate and AMPA but not NMDA receptor binding in mouse brain

et al. 2005

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“…Such increases could result directly from diminished capacity for astrocytic uptake of glutamate as a consequence of decreased expression of GLT-1. Reduced expression of GLT-1 and the consequently increased extracellular brain glutamate concentrations also offers a possible explanation for the observed decrease in densities (down regulation) of AMPA/kainate binding sites also described in this model of acute liver failure [10]. Diminished uptake of neuronally released glutamate by the astrocyte as a consequence of decreased expression of GLT-1 would therefore constitute further evidence of impaired neuron-astrocytic trafficking of glutamate, a phenomenon which has previously been proposed to contribute to the pathogenesis of hepatic encephalopathy based on neurochemical studies [4]and by 13C-NMR spectroscopy [16]in portacaval-shunted rats.…”

mentioning

confidence: 51%

Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure

Knecht

Michalak

Rose

et al. 1997

Neuroscience Letters

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169

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Knecht, K. et al., 1997. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neuroscience Letters, 229(3), The final publication is available at http://dx.doi.org/10.1016/S0304-3940 (97) ABSTRACTIt has been suggested that reduced astrocytic uptake of neuronally released glutamate contributes to the pathogenesis of hepatic encephalopathy in acute liver failure. In order to further address this issue, the recently cloned and sequenced astrocytic glutamate transporter GLT-1 was studied in brain preparations from rats with ischemic liver failure induced by portacaval anastomosis followed 24 h later by hepatic artery ligation and from appropriate sham-operated controls. GLT-1 expression was studied using reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of GLT-1 transcript was significantly decreased in frontal cortex at coma stages of acute liver failure. Western blotting using a polyclonal antibody to GLT-1 revealed a concomitant decrease in expression of transporter protein in the brains of rats with acute liver failure. Reduced capacity of astrocytes to reuptake neuronally released glutamate, resulting from a GLT-1 transporter deficit and the consequently compromised neuron-astrocytic trafficking of glutamate could contribute to the pathogenesis of hepatic encephalopathy and brain edema, two major complications of acute liver failure.Keywords GLT-1; hepatic encephalopathy; Astrocytes; Neuron-astrocyte trafficking; Gene expression; RT-PCR; Western blottingAcute liver failure resulting from viral infections or ingestion of toxic substances results in severe neurological impairment progressing through stupor and coma within hours or days. The pathophysiologic mechanisms responsible for hepatic encephalopathy (HE) in acute liver failure are unknown but deficits of neurotransmission rather than primary cerebral energy failure are currently considered to be implicated [1 and 3]. In this regard, there is increasing evidence to suggest that abnormalities of the glutamate neurotransmitter system are involved in the pathogenesis of HE in acute liver failure. Brain concentrations of glutamate are reduced in both human [13]and experimental [7 and 17] acute liver failure and recent studies using in vivo cerebral microdialysis in both rats 2 and 9and rabbits [5]with acute (ischemic) liver failure have consistently revealed increased extracellular brain concentrations of glutamate. It was suggested that the increased extracellular concentrations of glutamate in the brain of these animals was the consequence of decreased astrocytic uptake [9]. The major high affinity astrocytic transporter for glutamate, GLT-1, has recently been cloned and sequenced 12 and 14. In order to directly assess glutamate uptake capacity in the brain in acute liver failure, GLT-1 gene and protein expression were measured in frontal cortex of rats with acute (ischemic) liver failure.Male, Sprague-Dawley rats (175-200 g) were anesthetized with halothane and an end-to-side portacaval ...

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“…17,30,31 Based on these findings, it has been proposed that increased extracellular brain glutamate could be implicated in the pathogenesis of hepatic encephalopathy and brain edema in ALF. 32 In this same model of ALF, it has been proposed that increased extracellular glutamate concentrations in brain are the consequence of a loss in expression of the astrocytic glutamate transporter, GLT-1. 33 Furthermore, studies in cultured astrocytes suggest that the loss of glutamate transporter expression on astrocytes may be mediated by exposure to ammonia.…”

Section: Discussionmentioning

confidence: 99%

Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure

et al. 2000

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Mild hypothermia is effective in the prevention of brain edema associated with cerebral ischemia and traumatic brain injury. Brain edema is also a serious complication of acute liver failure (ALF). To assess the effectiveness of hypothermia in ALF, groups of rats were subjected to hepatic devascularization (portacaval anastomosis, followed 48 hours later by hepatic artery ligation), and body temperatures were maintained at either 35ЊC (hypothermic) or 37ЊC (normothermic). A major cause of death in patients with acute liver failure (ALF) is brain herniation resulting from raised intracranial pressure caused by a progressive increase in brain water content. 1 It has been estimated that up to 40% of patients with ALF die while on the waiting list for liver transplantation, 2 in whom, in almost all cases, death results from brain herniation. Despite several decades of investigation, the pathophysiological mechanisms responsible for the central nervous system consequences of ALF have not been fully elucidated. However, ammonia remains a prime candidate. Hyperammonemia is a consistent finding in experimental animal models of ALF resulting from hepatectomy, 3 hepatic devascularization, 4,5 or toxic liver injury 6 , and, in these cases, brain edema is invariably observed. In ALF, brain ammonia may reach millimolar concentrations, 7 and exposure of various in vitro brain preparations to millimolar concentrations of ammonia results in significant cell swelling. 8,9 Hyperammonemia is a feature of Reye' s Syndrome 10 and congenital urea cycle enzymopathies, 11 conditions in which cerebral edema is also consistently observed.Previous studies showed that hypothermia extended the survival time and prevented the development of brain edema in rats with ALF. 12 Furthermore, mild hypothermia (33°C-35°C) has been shown to be neuroprotective in experimental models of traumatic 13 and ischemic brain injury. 14 In the case of the latter, it was suggested that the beneficial effects of hypothermia were the result of inhibition of the release of neurotransmitters, rather than of an effect on cerebral energy metabolism. 15 The goals of the present investigation, therefore, were to study the effect of hypothermia on the development of hepatic encephalopathy and brain edema in relation to blood and cerebrospinal fluid (CSF) ammonia levels, and to extracellular glutamate and glutamine concentrations in rats with ALF caused by hepatic devascularization. MATERIALS AND METHODSO-phthaldialaldehyde reagent solution, 2-mercaptoethanol, Trisacetate, Ringer' s solution constituents, and amino acid standards were purchased from Sigma Chemical Co. (St. Louis, MO). Sodium phosphate (monobasic), methanol (high-performance liquid chromatography [HPLC]-grade), and tetrahydrofuran (HPLC-grade) were obtained from Anachemia (Montreal, Quebec, Canada). Doubledistilled deionized water was used for preparation of standard amino acid solutions and buffers. The mobile phase used for HPLC was filtered through 0.45-mm-pore-size membrane filters (Millipore Corp., B...

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Selective Loss of Binding Sites for the Glutamate Receptor Ligands [3H]Kainate and (S)–[3H]5–Fluorowillardiine in the Brains of Rats With Acute Liver Failure

Cited by 44 publications

References 25 publications

Taurine-transporter gene knockout-induced changes in GABAA, kainate and AMPA but not NMDA receptor binding in mouse brain

Taurine-transporter gene knockout-induced changes in GABAA, kainate and AMPA but not NMDA receptor binding in mouse brain

Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure

Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure

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