Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuropeptide diazepam binding inhibitor (DBI) is an endogeneous allosteric modulator of gamma-aminobutyric acid (GABA) receptors at the benzodiazepine recognition site. Recent theories on the neurochemical cause for hepatic encephalopathy have implicated activation of inhibitory neurotransmitter GABA systems. In 20 patients with hepatic disease, blood and cerebrospinal fluid (CSF) levels of ammonia and amino acids were measured. As in previous studies there was a selective elevation of CSF amino acids as well as a correlation between CSF glutamine levels and encephalopathy. CSF DBI levels were maximally elevated 5-fold in patients with hepatic encephalopathy, but they were normal in those patients with liver disease not associated with changes in mental status and in patients with nonhepatic encephalopathy. Levels of DBI correlated with the clinical staging of hepatic encephalopathy. These data suggest that DBI may participate in the modulation of cerebral function in hepatic encephalopathy.
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PMID:Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy. 254 47

Observing animal models of fulminant hepatic failure lead to the hypothesis of a GABAergic origin of the comatose state in hepatic encephalopathy (HE). The hypothesis of hyperstimulation of gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptors in HE has been tested with a BZ antagonist (flumazenil, Anexate) on 7 patients suffering from severe HE. The standard EEG has been recorded 30 min before and after slow IV perfusion of 1 mg flumazenil. Although we did not observe a complete EEG normalization, a significant improvement of EEG was observed after only a few minutes in 6 out of the 7 cases studied. Modification of the reactivity parallels clinical improvement of encephalopathy. These effects persist mostly 4 h after perfusion. The results are consistent with the hypothesis of hyperstimulation of GABA-BZ receptors in HE. The positive effect of flumazenil on vigilance level should encourage its use in chronic hepatic encephalopathy.
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PMID:[Electroencephalographic study of the effect of a benzodiazepine antagonist in hepatic encephalopathy]. 255 9

Three separate, but allosterically interacting, sites on the gamma-aminobutyric acid (GABA) supramolecular complex in the brain were pharmacologically blocked in rabbits with hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure to determine whether decreased GABAergic neurotransmission can ameliorate the syndrome of hepatic encephalopathy. Bicuculline (a GABAA receptor blocker), Ro 15-1788 (a benzodiazepine receptor antagonist), or isopropylbicyclophosphate (a chloride channel blocker) consistently induced a transient but unequivocal decrease in the clinical severity of the encephalopathy and also corrected the abnormal pattern of the visual evoked response associated with hepatic encephalopathy. Rabbits with hepatic encephalopathy exhibited increased resistance to the convulsive effects of bicuculline. In encephalopathies induced in rabbits by gamma-vinyl-GABA (an inhibitor of GABA catabolism) or diazepam (a benzodiazepine receptor agonist), abnormalities of the visual evoked response similar to those found in hepatic encephalopathy occurred and were corrected by bicuculline and Ro 15-1788, respectively. These findings suggest that in hepatic encephalopathy due to fulminant hepatic failure (a) there is increased GABAergic tone, (b) an amelioration of encephalopathy can be induced by blockade of GABA or benzodiazepine receptors, (c) benzodiazepine receptor antagonists may be of clinical value in the management of hepatic encephalopathy, and (d) an endogenous substance with GABA potentiating properties may be present in hepatic encephalopathy.
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PMID:Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure. 282 Aug 28

High affinity recognition sites for benzodiazepines are part of the gamma-aminobutyric acid (GABA) supramolecular complex on the plasma membrane of neurons in the mammalian brain. Synthetic agonist benzodiazepines promote GABA-ergic neurotransmission, and hence the hypnotic and anxiolytic effects of this class of drugs, by binding to these sites. A normal physiological role for these binding sites is unknown, and an endogenous ligand for benzodiazepine receptors has not been definitely identified in normal animals. In animals and human beings with hepatic encephalopathy, however, benzodiazepine receptor antagonists have induced amelioration of the encephalopathy, and an endogenous substance that competitively binds to benzodiazepine receptors has been found in cerebrospinal fluid. These findings suggest that an endogenous ligand for the benzodiazepine receptor with agonist properties contributes to hepatic encephalopathy by promoting GABA-ergic neurotransmission.
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PMID:Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy? 289 76

We measured neurotransmitter markers in autopsied brain of infants with glycine encephalopathy (GE). Because patients with GE develop intractable seizures, special attention was devoted to those neurotransmitter systems implicated in human epilepsy. Mean levels of glycine in the frontal cortex of GE patients were three times higher than control values. No abnormalities were observed for concentrations of gamma-aminobutyric acid (and related receptors), other major neurotransmitter amino compounds, or activities of cholineacetyltransferase and aspartate aminotransferase. Mean acetylcholinesterase activity was significantly elevated by 46%. As experimental data suggest, glycine markedly potentiates the action of the excitatory neurotransmitter glutamic acid. To the extent that the brain seizures in patients with GE can be explained by this mechanism, pharmacotherapy with excitatory amino acid antagonists may represent a new approach to the treatment of GE.
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PMID:Brain neurotransmitters in glycine encephalopathy. 290 30

We measured gamma-aminobutyric acid (GABA) and benzodiazepine binding in autopsied frontal cortex of 8 patients dying with dialysis encephalopathy (DE). No alteration in [3H] GABA binding was observed. However, a mild reduction (-23%, P less than 0.05) of [3H] flunitrazepam-binding density was found in DE cortex. The magnitude of this reduction was similar to that observed in frontal cortex of amygdala-kindled rats [10]. We suggest that a reduction in benzodiazepine receptor number, in combination with markedly reduced GABA concentration in DE cerebral cortex may contribute to some of the clinical features (especially seizures) characteristically observed in this syndrome.
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PMID:Brain gamma-aminobutyric acid and benzodiazepine receptor binding in dialysis encephalopathy. 299 77

Progabide, a recently introduced gamma-aminobutyric acid mimetic, is currently undergoing clinical evaluation for a variety of convulsive disorders. We describe a patient in whom severe hepatic failure developed after four weeks of Progabide therapy. The patient's course was marked by encephalopathy, jaundice, hypoglycemia, markedly elevated serum aminotransferase levels, and prolongation of the prothrombin time. Liver biopsy showed extensive hepatocellular necrosis. The patient recovered slowly after discontinuation of the drug. The finding of eosinophilia and increased serum IgE suggests an immunologically mediated mechanism for the Progabide-induced hepatic injury. Alternatively, the lipophilic moiety of Progabide may interact with hepatocyte cell membrane lipids leading to toxic injury. We conclude that Progabide may occasionally cause severe hepatic injury.
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PMID:Submassive hepatic necrosis associated with the use of progabide: a GABA receptor agonist. 334 28

Bulk-isolated astrocytes from rats with early hepatogenic encephalopathy (HE) induced with thioacetamide responded to the increase of potassium in the incubation medium from 5 mM to 75 mM with a markedly enhanced release of previously taken up [14C]gamma-aminobutyric acid ([14C]GABA). The process was not affected by omission of calcium and/or addition of EGTA to the incubation medium. Only a slight stimulation of GABA release by high potassium was observed in astrocytes from control rats. In contrast, histamine and histidine were vigorously released from control astrocytes in high-potassium medium, and their release was not enhanced by HE, indicating that the observed phenomenon is specific for GABA.
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PMID:Enhanced potassium-stimulated gamma-aminobutyric acid release by astrocytes derived from rats with early hepatogenic encephalopathy. 358 44

We attempted to produce a rat model of brain aluminum toxicity in order to explore whether or not aluminum accumulation produces the neurochemical changes observed in brains of patients who die with dialysis encephalopathy. Daily subcutaneous injection of Al(OH)3 caused marked elevation of serum aluminum concentrations, but did not increase brain aluminum contents, either in rats with normal renal function, or in rats with unilateral or 5/6 nephrectomies. LiCl pretreatment, which has been reported to cause irreversible renal failure, did not impair renal function nor aid in achieving elevated brain aluminum contents. No reductions in brain contents of gamma-aminobutyric acid (GABA) or in glutamic acid decarboxylase (GAD, E.C.4.1.1.15) and choline acetyltransferase (ChAT, E.C.2.3.1.6) activities were observed in aluminum-treated rats. We conclude that the rat is not a suitable laboratory animal to explore the role of aluminum toxicity in causing the GABA and ChAT deficits present in brains of hemodialyzed human patients.
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PMID:Inability to produce a model of dialysis encephalopathy in the rat by aluminum administration. 360 Sep 63

Cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in a dog model of spontaneous chronic portosystemic encephalopathy. Dogs with congenital portacaval shunts (intra- or extra-hepatic) develop neurological features of abnormal psychomotor behaviour and depressed consciousness that are consistent with the symptoms of chronic portosystemic encephalopathy in humans. In the five dogs studied, plasma ammonia was elevated, as was CSF tryptophan, both usual biochemical abnormalities in portosystemic encephalopathy. CSF levels of GABA in five dogs with portosystemic encephalopathy (100 +/- 13 pmol/ml) were not significantly different from those in five control dogs (96 +/- 14 pmol/ml). CSF levels of GABA were not altered after ammonia infusion. If enhanced GABA-ergic neurotransmission, due to influx of gut-derived GABA into the brain, is responsible for the pathophysiology of chronic portosystemic encephalopathy in this model, it is not reflected by increased levels of GABA in CSF.
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PMID:Cerebrospinal fluid gamma-aminobutyric acid levels in dogs with chronic portosystemic encephalopathy. 379 75


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