Portal-Systemic Encephalopathy in Dogs: Changes in Brain GABA Receptors and Neurochemical Correlates

Baraldi, Mario; Zeneroli, Maria Luisa; Ventura, Emily E.; Pinelli, Giovanni; Ricci, P; Santi, M. M. De; Racagni, Giorgio; Iuliano, E.; Casciarri, I.; Germini, M.; Cavalletti, Ennio; Tofanetti, G.

doi:10.1159/000410831

Cited by 6 publications

(4 citation statements)

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“…Obviously, our experiments cannot rule out the possibility that HE may be largely or partially due to an increased sensitivity of GABA receptors. Changes of GABA recognition sites have been described in animal models of HE such as rats (31) or rabbits (1) injected with galactosarnine and in dogs treated with dimethylnitrosamine, followed by portocaval anastomosis (32). In humans, the amelioration of HE obtained in a few patients (Scollo-Laviezzari G. and Steinman, E., Lancet 1985; 1:1324, Correspondence; Bansky, G. et al, Lancet 1985; 1: 1325, Correspondence) with the administration of benzodiazepine antagonist has been interpreted as suggesting that the GABA receptor complex is involved in the pathogenesis of HE.…”

Section: Discussionmentioning

confidence: 99%

Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Moroni¹,

Riggio²,

Carlà³

et al. 1987

Hepatology

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The aim of the study was to verify the role of gamma-aminobutyric acid in the pathogenesis of hepatic encephalopathy occurring in cirrhotic patients by attempting to correlate plasma and cerebrospinal fluid content of authentic gamma-aminobutyric acid with the neurological manifestations of hepatic encephalopathy. For this purpose, plasma and cerebrospinal fluid gamma-aminobutyric acid levels were measured by means of mass fragmentography in 17 cirrhotic patients with hepatic encephalopathy and in 6 cirrhotics without neurological symptoms. Moreover, in all patients, a second sample was obtained during the clinical course of hepatic encephalopathy. The mean plasma and cerebrospinal fluid gamma-aminobutyric acid levels were not different in patients with or without hepatic encephalopathy and did not change during the evolution of the neurological symptoms. The lack of changes in the gamma-aminobutyric acid content in plasma and cerebrospinal fluid during hepatic encephalopathy is in contrast with the hypothesized importance of increased entry into the brain of gamma-aminobutyric acid in the pathogenesis of hepatic encephalopathy.

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Section: Discussionmentioning

confidence: 99%

Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Moroni¹,

Riggio²,

Carlà³

et al. 1987

Hepatology

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“…There have been many studies of brain GABA receptors in different animal models of acute and chronic HE and in human patients. Although some studies have reported alterations in GABA receptor binding (Baraldi and Zeneroli, 1982;Schafer et al, 1983;Ferenci et al, 1983Ferenci et al, , 1988Baraldi et al, 1984;Wysmyk-Cybula et al, 1986;, the direction and type of changes found have not been consistent. The majority of studies have found no significant alterations in brain GABA receptor density or affinity in animal models or patients with HE (Zanchin et al, 1984;Thompson et al, 1985;Ferenci et al, 1987;La1 et al, 1987;Maddison et al, 1987aMaddison et al, ,b, 1988Roy et al, 1988;Butterworth et al, 1988;Watanabe et al, 1988;Rossle et al, 1989;Zimmermann et al, 1989).…”

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confidence: 94%

Alterations in Cortical [³H]Kainate and α‐[³H]Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Binding in a Spontaneous Canine Model of Chronic Hepatic Encephalopathy

Maddison

Watson

Dodd

et al. 1991

Journal of Neurochemistry

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Excitatory amino acid receptor binding parameters were investigated in a spontaneous dog model of chronic hepatic encephalopathy. L-[3H]Glutamate, (+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine maleate ([3H]MK-801), [3H]kainate, and alpha-[3H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding experiments were performed using crude cerebrocortical synaptosomal membrane preparations from dogs with congenital portosystemic encephalopathy (PSE) and control dogs. There was no change in the affinity or density of L-[3H]-glutamate or [3H]MK-801 binding sites in dogs with congenital PSE compared with control dogs. However, in the PSE dogs there was a significant reduction in the density of [3H]kainate binding sites compared with control dogs and abolition of the low-affinity [3H]AMPA binding site. The relative binding capacity of PSE synaptosomal membranes for [3H]kainate and [3H]AMPA was expressed as the ratio Bmax/KD. There was a significant inverse correlation between the Bmax/KD ratio for [3H]AMPA binding and the worst grade of encephalopathy experienced by each dog. These results suggest that there is a significant perturbation of cerebrocortical non-N-methyl-D-aspartate receptor binding in dogs with congenital PSE which may have relevance to the pathogenesis of hepatic encephalopathy.

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“…Fur thermore, experiments with large doses of systemically applied GABA have shown that the minute amounts which pass the bloodbrain barrier are rapidly eliminated from the CNS by active outward transport systems and/or are rapidly metabolized by the GABA-degrading enzyme GABA-T, which is present in high activities throughout the brain [12]. Thus, even in the presence of an altered blood-brain barrier, the high activi ties of GABA-T would prevent any signifi cant increase of brain GABA by elevated peripheral GABA levels [39]. This does, however, not exclude that increases of pe ripheral GABA levels have an effect on pe ripheral functions of the inhibitory transmit ter.…”

Section: Discussionmentioning

confidence: 99%

Marked Increases of Plasma Gamma-Aminobutyric Acid Concentrations in Cirrhotic Patients with Portacaval Shunts Are Not Associated with Alterations of Cerebral Functions

Löscher

Kretz²,

Karavias³

et al. 1991

Digestion

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Several previous studies have shown that the plasma concentration of γ-amino-butyric acid (GABA) is markedly increased in patients with hepatic encephalopathy, and it has been suggested that decreased metabolism of peripheral GABA might contribute to the cerebral dysfunctions observed. In the present study, plasma GABA-like activity was determined by a radioreceptor assay in 21 cirrhotic patients in whom, at least 2 months prior to the study, portocaval shunt surgery had been performed for treatment of recurrent variceal bleeding. Compared to 10 healthy volunteers, plasma GABA concentrations were increased in all cirrhotic patients, whereas most other amino acids, including those known to interfere with the GABA radioreceptor assay at elevated concentrations, were within the normal range. Despite an about 3- to 16-fold increase in individual GABA concentration, none of the patients showed clinical signs of overt hepatic encephalopathy on conventional neurologic (including EEG) and mental status examination. Furthermore, when a psychometric test system was used for evaluation of intellectual and psychomotor functions, all patients performed within the normal range and could not be distinguished from healthy volunteers. The data indicate that, at least in chronic liver disease, impaired metabolism of peripheral GABA does not lead to cerebral dysfunctions.

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Portal-Systemic Encephalopathy in Dogs: Changes in Brain GABA Receptors and Neurochemical Correlates

Cited by 6 publications

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Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Alterations in Cortical [³H]Kainate and α‐[³H]Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Binding in a Spontaneous Canine Model of Chronic Hepatic Encephalopathy

Marked Increases of Plasma Gamma-Aminobutyric Acid Concentrations in Cirrhotic Patients with Portacaval Shunts Are Not Associated with Alterations of Cerebral Functions

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Portal-Systemic Encephalopathy in Dogs: Changes in Brain GABA Receptors and Neurochemical Correlates

Cited by 6 publications

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Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Hepatic encephalopathy: Lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid

Alterations in Cortical [3H]Kainate and α‐[3H]Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Binding in a Spontaneous Canine Model of Chronic Hepatic Encephalopathy

Marked Increases of Plasma Gamma-Aminobutyric Acid Concentrations in Cirrhotic Patients with Portacaval Shunts Are Not Associated with Alterations of Cerebral Functions

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Alterations in Cortical [³H]Kainate and α‐[³H]Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Binding in a Spontaneous Canine Model of Chronic Hepatic Encephalopathy