G P Layrargues

Medsol Clinical Research Center, Florida, United States

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Publications (20)103.66 Total impact

  • Roger F. Butterworth Ph.D, Gilles Pomier Layrargues
    Hepatology 12/2005; 11(3):499 - 501. · 12.00 Impact Factor
  • Samir Ahboucha, Fadwa Araqi, Gilles Pomier Layrargues, Roger F Butterworth
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    ABSTRACT: Ammonia is a key factor in the pathogenesis of encephalopathies associated with liver failure. A direct effect of ammonia on GABAergic neurotransmission was proposed as a mechanism that may explain its neurotoxic effect on the basis of electrophysiological and biochemical studies performed in animal models of liver failure. In the present study, we investigated using a radiometric assay the effect of ammonia on the binding of GABA-A receptor ligands to membranes from normal human brains. Ammonium tartrate significantly decreased the maximal binding of [3H]flunitrazepam to well-washed frontal cortical membranes (366+/-63 fmol/mg protein in absence of ammonia versus 294.1+/-51 fmol/mg protein in presence of 2 mM ammonia; p<0.05). The efficacy of the effects of ammonia was within the millimolar range (IC50=4.8 mM). This effect was not seen in cerebellum or hippocampus. Ammonia exposure decreased the maximal binding of [3H]flumazenil (284.9+/-24.2 fmol/mg protein in absence of ammonia versus 146.4+/-15.6 fmol/mg protein in presence of 2 mM ammonia; p<0.01). This effect was seen with a greater potency (Imax=32.4%) and a lower IC50 (0.1 mM). Inhibition of [3H]flumazenil binding was significant in all brain regions. The apparent ammonia-induced decrease of [3H]flunitrazepam and [3H]flumazenil binding was due to a decrease in the binding affinities of these ligands for the benzodiazepine site. In contrast, ammonium tartrate exposure did not cause significant changes to the binding of [3H]muscimol in any brain region. These findings demonstrate that ammonia interacts negatively with components of the benzodiazepine-associated site at the GABA-A receptor complex in human brain in contrast to previous reports in the rat, and thus, does not support the notion that ammonia directly activates the GABA-A receptor complex resulting in increased GABAergic neurotransmission in human hepatic encephalopathy. These findings also suggest that positron emission tomography studies in cirrhotic patients using [11C]flumazenil may be underestimating GABA-A receptor sites depending upon the degree of hyperammonemia of the patient.
    Neurochemistry International 08/2005; 47(1-2):58-63. · 2.66 Impact Factor
  • Samir Ahboucha, Gilles Pomier Layrargues, Orval Mamer, Roger F Butterworth
    Annals of Neurology 08/2005; 58(1):169-70. · 11.19 Impact Factor
  • G P Layrargues
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    ABSTRACT: Hepatic encephalopathy is characterized by a variety of neurological symptoms. The occurrence of movement disorders is exceptional and is usually part of a clinical syndrome called acquired hepatocerebral degeneration, which is a subtype of chronic recurrent hepatic encephalopathy. The clinical picture is usually progressive and pathologic findings include regional astroglial and neuronal abnormalities found predominantly in cortex and basal ganglia. As for hepatic encephalopathy in general, the pathophysiology of this disorder is unknown but hyperammonemia and/or brain manganese overload may play a role. Medical treatment is often disappointing but in selected cases liver transplantation may be curative.
    Metabolic Brain Disease 07/2001; 16(1-2):27-35. · 2.33 Impact Factor
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    ABSTRACT: Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.
    Metabolic Brain Disease 01/1999; 13(4):311-7. · 2.33 Impact Factor
  • R F Butterworth, L Spahr, S Fontaine, G P Layrargues
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    ABSTRACT: Patients with chronic liver disease manifest a high incidence (> 75%) of pallidal signal hyperintensity on T1-weighted Magnetic Resonance Imaging (MRI), the intensity of which correlates with blood manganese levels and the presence of extrapyramidal symptoms. A major cause of pallidal hyperintensity on T1-weighted MRI is manganese deposition; chronic manganese intoxication in the absence of liver disease results in pallidal MR signal hyperintensity, in extrapyramidal symptoms and in selective effects on the dopaminergic neurotransmitter system in basal ganglia. Direct measurements in globus pallidus obtained at autopsy from patients with chronic liver disease who died in hepatic coma reveal 2 to 7-fold increases of pallidal manganese and a concomitant loss of dopamine D2 binding sites. Liver transplantation results in normalization of pallidal MR signals and of blood manganese levels. These findings suggest that (1) pallidal MR signal hyperintensity in patients with chronic liver disease is the result of manganese deposition and (2) alterations of dopaminergic function due to the toxic effects of manganese may contribute to the extrapyramidal symptoms in these patients.
    Metabolic Brain Disease 01/1996; 10(4):259-67. · 2.33 Impact Factor
  • G P Layrargues, D Shapcott, L Spahr, R F Butterworth
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    ABSTRACT: Concentrations of zinc, copper and manganese were measured by atomic absorption spectrometry in samples of globus pallidus obtained at autopsy from 9 patients with chronic liver disease and an equal number of age-matched controls. Manganese concentrations were significantly increased several fold (p < 0.01) in globus pallidus of liver disease patients accompanied by smaller but significant 2-fold increases of copper. Zinc concentrations, on the other hand, were within normal limits. Increased pallidal manganese offers a cogent explanation for the observed T1-weighted MRI signal hyperintensity in pallidum of cirrhotic patients. Increased copper content in brain suggests the existence of common pathophysiologic mechanisms in inherited (Wilson Disease) and acquired hepatocerebral disorders.
    Metabolic Brain Disease 01/1996; 10(4):353-6. · 2.33 Impact Factor
  • Kevin D. Mullen, Roger F. Butterworth, John Wells, Gilles Pomier‐Layrargues
    Hepatology 02/1995; 21(2). · 12.00 Impact Factor
  • Gastroenterology 01/1995; 108(4). · 12.82 Impact Factor
  • D D Mousseau, G P Layrargues, R F Butterworth
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    ABSTRACT: The distribution of [3H]tryptamine binding sites, in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE) and an equal number of age-matched control subjects free from hepatic, neurological, or psychiatric disorder, was investigated. Scatchard analysis demonstrated a heterogeneous distribution for this binding site, with the highest density being observed in hippocampus > frontal cortex = caudate nucleus > temporal cortex = cerebellum. When comparing [3H]tryptamine binding site densities in control brain tissue with that in brain tissue from patients with HE, significant decreases in densities were observed in the frontal cortex (by 56%, p < 0.001), hippocampus (by 43%, p < 0.001), and caudate nucleus (by 41%, p < 0.01) of the HE group. Binding site affinities were within normal limits. The findings of decreased densities of [3H]tryptamine binding sites taken in conjunction with previous reports of increased CSF and brain tryptamine concentrations in HE suggest a pathogenic role for this neuroactive amine in HE resulting from chronic liver failure.
    Journal of Neurochemistry 03/1994; 62(2):621-5. · 3.97 Impact Factor
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    ABSTRACT: The binding parameters of [3H]SCH 23390 and [3H]spiperone (radioligands for dopamine D1 and D2 receptors, respectively) were investigated in autopsied frontal cortex, caudate nucleus and globus pallidus/putamen of cirrhotic patients who died in hepatic coma as well as in age- and sex-matched controls. Specific [3H]SCH 23390 binding site densities were unchanged in all regions; in contrast, specific [3H]spiperone binding site density was decreased (by 44%, P < 0.001) in the globus pallidus/putamen of patients with HE. Decreased densities of pallidal D2 binding sites could relate to the motor dysfunctions commonly encountered in human HE.
    Neuroscience Letters 11/1993; 162(1-2):192-6. · 2.03 Impact Factor
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    ABSTRACT: Using radioenzymatic assays, activities of MAOA and MAOB were measured in autopsied brain tissue from cirrhotic patients who died in hepatic coma and in material from an equal number of age-matched subjects who were free from hepatic, neurological or psychiatric disorders. Activities of both MAOA and MAOB were significantly increased in frontal cortex and caudate nucleus, two brain regions shown previously to be the site of functional and morphological alterations of astrocytes and increased concentrations of the acid metabolites of dopamine and serotonin. These findings suggest that increased monoamine metabolism and subsequent modifications of monoaminergic synaptic function could contribute to the pathogenesis of hepatic encephalopathy.
    Brain Research 10/1993; 621(2):349-52. · 2.88 Impact Factor
  • Joel Lavoie, Gilles Pomier Layrargues, Roger F. Butterworth
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    ABSTRACT: Peripheral-type benzodiazepine receptors were evaluated using the specific ligand [3H]-PK 11195 in brain homogenates from nine cirrhotic patients who died in hepatic coma and from an equal number of age-matched control subjects. Histopathological studies showed evidence of severe Alzheimer type II astrocytosis in the brains of all cirrhotic patients. Saturation-binding assays revealed a single saturable binding site for [3H]-PK 11195 in brain, with affinities in the 2- to 3-nmol/L range. Diazepam was found to be a relatively potent inhibitor of 3H-PK 11195 binding (IC50 = 253 nmol/L), whereas the central benzodiazepine antagonist Ro 15-1788 displaced 3H-PK 11195 binding with low affinity (IC50 greater than 40 mumols/L). Densities of [3H]-PK 11195 binding sites were found to be increased by 48% (p less than 0.01) and 25% (p less than 0.05) in frontal cortex and caudate nuclei, respectively, from cirrhotic patients. Densities of [3H]-PK 11195 binding sites in frontal cortex from two nonencephalopathic cirrhotic patients were not significantly different from control values. No concomitant changes of affinities of these binding sites were observed. Because it has been suggested that peripheral-type benzodiazepine receptors may be localized on mitochondrial membranes and may therefore be involved in cerebral oxidative metabolism, the alterations observed in this study could be of pathophysiological significance in hepatic encephalopathy.
    Hepatology 06/1990; 11(5):874-8. · 12.00 Impact Factor
  • R F Butterworth, G Pomier Layrargues
    Hepatology 04/1990; 11(3):499-501. · 12.00 Impact Factor
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    ABSTRACT: Alterations in the metabolism of monoamine neurotransmitters have been proposed to be involved in the development of the hepatic encephalopathy (HE) associated with experimental and human liver failure. In order to evaluate this hypothesis, the monoamines and some of their metabolites were measured in homogenates of caudate nucleus (CAU), prefrontal (PFCo) and frontal cortex (FCo) dissected from brains obtained at autopsy from nine cirrhotic patients who had died in hepatic coma and an equal number of control subjects, free from neurological, psychiatric and hepatic disorders, matched for age and time interval from death to freezing of autopsied brain samples. Monoamine measurements were performed by high-performance liquid chromatography with ion-pairing and electrochemical detection after a simple extraction procedure. In all three regions investigated, concentrations of dopamine (DA) were unchanged in cirrhotic patients vs controls while its metabolites, 3-methoxytyramine (3-MT) and homovanillic acid (HVA) were selectively affected i.e. 3-MT was found to be increased in CAU, while HVA levels were increased in FCo and CAU. DOPAC was also found to be unchanged in CAU. Noradrenaline (NA) levels were greatly increased in PFCo and FCo of cirrhotic patients but remained unchanged in CAU. No significant differences in the concentrations of either serotonin (5-HT) or of its precursor 5-hydroxytryptophan (5-HTP) were found in any of the three regions studied. However, 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, was increased in PFCo and CAU of cirrhotic patients. These findings show that selective alterations of catecholamine and 5-HT systems are involved in human HE and therefore, they may play an important role in the pathogenesis of certain neurological symptoms associated with this encephalopathy.
    Neurochemical Research 10/1989; 14(9):853-9. · 2.13 Impact Factor
  • M Bergeron, G P Layrargues, R F Butterworth
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    ABSTRACT: Concentrations of the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine and the aromatic amino acids (AAAs) phenylalanine and tyrosine were measured in three areas of dissected brain tissue obtained at autopsy from nine cirrhotic patients who died in hepatic encephalopathy. The controls were an equal number of subjects free from neurological, psychiatric or hepatic diseases, matched for age and time interval from death to freezing of autopsied brain samples. Amino acids were measured using high-performance liquid chromatography with fluorimetric detection. In brain tissue of cirrhotic patients, no changes in BCAA concentrations were observed compared with controls. On the other hand, phenylalanine levels were found to be increased 141% in prefrontal cortex, 86% in frontal cortex and 26% in caudate nucleus, and tyrosine content was increased by 71% in prefrontal cortex and 28% in frontal cortex with no significant increase in caudate nucleus. Alterations in the concentration of AAAs may lead to disturbances of monoamine neurotransmitters in brain. Such changes could play a role in the pathogenesis of hepatic encephalopathy resulting from chronic liver disease in man.
    Metabolic Brain Disease 10/1989; 4(3):169-76. · 2.33 Impact Factor
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    ABSTRACT: Activities of the -aminobutyric acid (GABA) and cholinergic nerve-terminal marker enzymes glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) as well as the astrocytic enzyme glutamine synthetase (GS) were measured in homogenates of dissected brain tissue obtained at autopsy from nine cirrhotic patients dying in hepatic encephalopathy and an equal number of control subjects matched for age, agonal status, and time interval from death to freezing of autopsied material. GAD activities varied as a function of agonal status in control samples, confirming a previous report, but were unchanged in brain tissue from cirrhotic patients, suggesting no loss of integrity of presynaptic GABA nerve terminals in this disease. On the other hand, GS activities were selectively decreased by 25% (P < 0.01)="" in="" caudate="" nuclei="" of="" cirrhotic="" patients,="" reflecting,="" no="" doubt,="" the="" severe="" astrocytosis="" consistently="" observed="" in="" this="" brain="" structure.="" cat="" activities,="" expressed="" per="" milligram="" of="" protein,="" were="" found="" to="" be="" increased="" by="" 30%="">P < 0.01)="" in="" the="" prefrontal="" cortex="" of="" cirrhotic="" patients.="" whether="" such="" changes="" result="" from="" a="" relative="" increase="" in="" cat="" as="" a="" consequence="" of="" losses="" of="" astrocytic="" protein="" or="" reflect="" altered="" cholinergic="" function="" in="" hepatic="" encephalopathy="" associated="" with="" chronic="" liver="" disease="" awaits="" further="">
    Metabolic Brain Disease 11/1987; 2(4):283-290. · 2.33 Impact Factor
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    ABSTRACT: Brain tissue was obtained at autopsy from nine cirrhotic patients dying in hepatic coma and from an equal number of controls, free from neurological, psychiatric, or hepatic diseases, matched for age and time interval from death to freezing of dissected brain samples. Glutamine, glutamate, aspartate, and gamma-aminobutyric acid (GABA) levels were measured in homogenates of cerebral cortex (prefrontal and frontal), caudate nuclei, hypothalamus, cerebellum (cortex and vermis), and medulla oblongata as their o-phthalaldehyde derivatives by HPLC using fluorescence detection. Glutamine concentrations were found to be elevated two- to fourfold in all brain structures, the largest increases being observed in prefrontal cortex and medulla oblongata. Glutamate levels were selectively decreased in prefrontal cortex (by 20%), caudate nuclei (by 27%), and cerebellar vermis (by 17%) from cirrhotic patients. On the other hand, GABA content of autopsied brain tissue from these patients was found to be within normal limits in all brain structures. It is suggested that such region-selective reductions of glutamate may reflect loss of the amino acid from the releasable (neurotransmitter) pool. These findings may be of significance in the pathogenesis of hepatic encephalopathy resulting from chronic liver disease.
    Journal of Neurochemistry 10/1987; 49(3):692-7. · 3.97 Impact Factor
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    ABSTRACT: Measurement of amino acids in brain tissue obtained at autopsy from cirrhotic patients dying in hepatic coma revealed a threefold increase in glutamine and a concomitant decrease in brain glutamate. The GABA levels were found to be unaltered. Studies using an animal model of portal-systemic encephalopathy gave similar results. Glutamic acid decarboxylase (GAD) activities were within normal limits, both in the brains of cirrhotic patients and portocaval-shunted rats. A previous study reported normal [3H]GABA binding to synaptic membrane preparations from cerebral cortex in these animals. Taken together, these findings suggest that cerebral GABA function is not impaired in hepatic encephalopathy associated with chronic liver disease and portal-systemic shunting. On the other hand, there is evidence to suggest that the releasable pool ofglutamate may be depleted in brain in hepatic encephalopathy. Data consistent with this hypothesis include: (i) Reduction in the evoked release of endogenous glutamate by superfusion of hippocampal slices with pathophysiological levels of ammonia; (ii) ammonia-induced reduction of glutamatergic neurotransmission; and (iii) an increase in the number of [3H]glutamate binding sites in synaptic membrane preparations from hyperammonemia rats and from rats with portocaval shunts. Such neurochemical changes may be of pathophysiological significance in hepatic encephalopathy.
    Neurochemical Pathology 02/1987; 6(1):131-144.
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    ABSTRACT: There is substantial clinical and experimental evidence to suggest that ammonia toxicity is a major factor in the pathogenesis of hepatic encephalopathy associated with subacute and chronic liver disease. Ammonia levels in patients with severe liver disease are frequently found to be elevated both in blood and cerebrospinal fluid (csf). Hepatic encephalopathy results in neuropathological damage of a similar nature (Alzheimer type II astrocytosis) to that found in patients with congenital hyperammonemia resulting from inherited defects of urea cycle enzymes. Following portocaval anastomosis in the rat, blood ammonia concentration is increased 2-fold, and brain ammonia is found to be increased 2–3-fold. Administration of ammonia salts or resins to rats with a portocaval anastomosis results in coma and in Alzheimer type II astrocytosis. Since the CNS is devoid of effective urea cycle activity, ammonia removal by brain relies on glutamine formation. Cerebrospinal fluid and brain glutamine are found to be significantly elevated in cirrhotic patients with encephalopathy and in rats following portocaval anastomosis. In both cases, glutamine is found to be elevated in a region-dependent manner. Several mechanisms have been proposed to explain the neurotoxic action of ammonia. Such mechanisms include: (i) Modification of blood-brain barrier transport; (ii) alterations of cerebral energy metabolism; (iii) direct actions on the neuronal membrane; and (iv) decreased synthesis of releasable glutamate, resulting in impaired glutamatergic neurotransmission.
    Neurochemical Pathology 6(1):1-12.

Publication Stats

891 Citations
103.66 Total Impact Points

Institutions

  • 1999
    • Medsol Clinical Research Center
      Florida, United States
  • 1990–1995
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 1990–1993
    • Université de Montréal
      • Department of Medicine
      Montréal, Quebec, Canada