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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic encephalopathy is considered to be a reversible metabolic encephalopathy, which occurs as a complication of hepatocellular failure and is associated with increased portal-systemic shunting of gut-derived nitrogenous compounds. Its manifestations are most consistent with a global depression of CNS function, which could arise as a consequence of a net increase in inhibitory neurotransmission, due to an imbalance between the functional status of inhibitory (e.g., GABA) and excitatory (e.g., glutamate) neurotransmitter systems. In liver failure, factors that contribute to increased GABAergic tone include increased synaptic levels of GABA and increased brain levels of natural central benzodiazepine (BZ) receptor agonists. Ammonia, present in modestly elevated levels, may also augment GABAergic tone by direct interaction with the GABAA receptor, synergistic interactions with natural central BZ receptor agonists, and stimulation of astrocytic synthesis and release of neurosteroid agonists of the GABAA receptor. Thus, there is a rationale for therapies of HE that lower ammonia levels and incrementally reduce increased GABAergic tone towards the physiologic norm.
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PMID:Pathogenesis of hepatic encephalopathy. 1123 1

Therapeutic management in hepatic encephalopathy depends on its etiology as well as progression degree. Both in acute and chronic encephalopathy one should tend to establish probable causes and try to eliminate them. Cutting down on proteins in diet is one of the most important suggestions in chronic hepatic encephalopathy. In order to reduce intestinal production of ammonia, non-absorbable disaccharides (lactulose), antibiotics (neomycin) and sodium benzoate are the most commonly used. Branched chain amino acids administered orally or parenterally may be useful in improving patient's condition and restoring the balance of blood amino acids. The GABA-benzodiazepine receptor theory led to application of its antagonists, such as flumazenil, in the management of hepatic encephalopathy. However, providing a proper treatment is not easy due to unstable and often not very characteristic course of hepatic encephalopathy. What is more, clinical trials of some drugs used in the treatment of hepatic encephalopathy do not confirm their effectiveness.
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PMID:[Therapeutic management of hepatic encephalopathy]. 1223 97

Increased concentrations of leucine and its respective ketoacid alpha-ketoisocaproate (KIC) in plasma and cerebrospinal fluid are related to acute and reversible encephalopathy in patients with maple syrup urine disease. We studied electrophysiological properties of primary dissociated rat neurons at increased extracellular concentrations of leucine and KIC (1-10 mM). Spontaneous neuronal network activity was reversibly reduced or blocked by leucine as well as by KIC in a dose-dependent manner. Simultaneous incubation with both substances led to a minor inhibition compared to the effect of each substance alone. Neuronal resting potential, voltage dependent Na(+) (I(Na)) and K(+) (I(K)) currents, the GABA- and glycine-elicited membrane currents, and glutamate-induced intracellular Ca(2+) increase of single neurons, however, were unaffected by both substances. We conclude that acute neuronal network dysfunction in maple syrup urine disease is mainly based on an imbalance of the presynaptic glutamatergic/GABAergic neurotransmitter concentrations or their release.
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PMID:Disturbance of cultured rat neuronal network activity depends on concentration and ratio of leucine and alpha-ketoisocaproate: implication for acute encephalopathy of maple syrup urine disease. 1253 93

Acute liver failure (ALF) results in alterations of energy metabolites and of glucose-derived amino acid neurotransmitters in brain. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in relation to the severity of encephalopathy and brain edema in rats with ALF because of hepatic devascularization. Early (precoma) stages of encephalopathy were accompanied by significant 2- to 4.5-fold (P <.001) increases of total brain glutamine and lactate concentrations. More severe (coma) stages of encephalopathy and brain edema led to a further significant increase in brain lactate but no such increase in glutamine. Furthermore, (13)C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-(13)C]glucose resulting in 2.5-fold increased fractional (13)C enrichments in lactate at coma stages. [2-(13)C]glutamine, synthesized through the astrocytic enzyme pyruvate carboxylase, increased 10-fold at precoma stages but showed no further increase at coma stages of encephalopathy. (13)C-label incorporation into [4-(13)C]glutamate, synthesized mainly through neuronal pyruvate dehydrogenase, was selectively reduced at coma stages, whereas brain GABA synthesis was unchanged at all time points. In conclusion, increased brain lactate synthesis and impaired glucose oxidative pathways rather than intracellular glutamine accumulation are the major cause of brain edema in ALF. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates could be valuable in the elucidation of the cerebral metabolic consequences of ALF in humans.
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PMID:Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study. 1254 Jul 93

There appears to be a consensus that hepatic encephalopathy (HE) is a metabolic encephalopathy with a multifactorial pathogenesis. One of the factors considered to be important in the pathogenesis of HE is ammonia. However, the mechanisms by which ammonia contributes to the manifestations of HE remain poorly defined. Ammonia could be more definitively implicated in the pathogenesis of HE if its effects can be shown to lead to an enhancement of inhibitory neurotransmission. In this context the effects of ammonia on the GABA (gamma-aminobutyric acid) neurotransmitter system may be relevant. Ammonia, at the modestly increased concentrations that commonly occur in precoma HE (0.15 mM-0.75 mM), has been shown to increase GABA-induced chloride current in cultured neurons, probably by modifying the affinity of the GABA(A) receptor for GABA. Comparable ammonia concentrations also enhanced synergistically the binding of a GABA agonist and a benzodiazepine (BZ) agonist to the GABA(A) receptor complex, phenomena which would enhance the neuroinhibitory effects of these ligands. Also, GABA increased the potency of ammonia-induced enhancement of the binding of a BZ agonist to the GABA(A) receptor complex, and brain levels of BZ agonists are elevated in liver failure. In addition, ammonia has been shown to inhibit astrocytic uptake of GABA by 30%-50%, an effect which would increase the synaptic availability of GABA at GABA(A) receptors. Furthermore, increased ammonia concentrations upregulate the peripheral-type benzodiazepine receptor in the outer membrane of astroglial mitochondria, thereby enhancing astrocytic mitochondrial synthesis and release of neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA(A) receptor complex, on which there are specific binding sites for neurosteroids, that are distinct from those for BZs and barbiturates. Tetrahydroprogesterone and tetrahydrodeoxycorticosterone levels were found to be increased in a mouse model of acute liver failure, and, when THP or THDOC was injected into normal mice, sedation and Alzheimer type II astrocytic changes in the cortex, striatum, and hypothalmus were induced. Each of these direct or indirect effects of ammonia on the GABA neurotransmitter system has the potential of increasing inhibitory neurotransmission, and, hence, contributing to the manifestations of HE.
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PMID:Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy. 1260 4

Tiagabine (TGB), a novel GABA reuptake inhibitor antiepileptic drug, has been reported to induce nonconvulsive status epilepticus (NCSE) in patients with generalized or partial onset seizures. We describe six patients with refractory partial epilepsy treated with add-on TGB. They developed acute intermittent or progressive chronic confusion associated with diffuse slowing of the electroencephalogram (EEG), shortly after an increase in dose of TGB. This remitted in each situation after reduction of the daily dose. The possibility of nonconvulsive status epilepticus or toxic encephalopathy is discussed.
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PMID:Clinical and EEG findings in six patients with altered mental status receiving tiagabine therapy. 1279 36

Hepatic encephalopathy is a frequent complication of cirrhosis. Portal-systemic shunts and depression of hepatic function are the primary underlying abnormalities. Arterial blood ammonia levels are frequently elevated during hepatic encephalopathy and are lower when a clinical improvement is established. Glutamine synthesis is part of the metabolic pathway for ammonia cerebral detoxification that induces ATP and glutamate (excitatory neurotransmitter) depletion. Plasma levels of branched chain amino acids are reduced in patients with cirrhosis, this event allows aromatic amino acids to cross the hemato-liquoral barrier through exchange with glutamine. Cerebral excess of aromatic amino acids promotes the synthesis of octopamine and feniletiletanolamine, weak neurotransmitters. Benzodiazepine-like substances may affect GABA-ergic transmission by interacting with their receptors on the GABA-benzodiazepine complex. Therapy is aimed at controlling the events that may precipitate the acute encephalopathy, at reducing the ammonia levels, and correcting the neurotransmission abnormalities.
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PMID:[Hepatic encephalopathy. Pathogenesis and therapy]. 1284 6

An increase in GABA uptake by isolated rat brain synaptic endings as well as a decrease of pharmacologically active GABA analogue muscimol specific binding have indicated a physiologically drastic failure in realization of GABA-mediated inhibitory effects in CNS induced by diabetic encephalopathy. In spite of the impairment of inhibitory function of GABAergic transmission in diabetes a crucial activation of benzodiazepine receptors was determined, as it is tested by the increase in specific binding of flunitrazepam by synaptic membranes. This increase may play an important role in endogenous control of neural activity associated with the factors undefined so far. Using the approach that GABA, and several synthetic GABA agonists, appear to increase the affinity of the benzodiazepine recognition sites for such ligands, presumably by some allosteric mechanism, the findings concerning the in vitro binding assay technique confirm at least some of the functional characteristics observed between GABA and benzodiazepine receptors in vivo under pathological conditions. Indeed, the absence of activating effect on the affinity of flunitrazepam specific binding in the presence of micromolar concentrations of exogenous GABA implicate diabetes-induced alterations in coupling GABA- and benzodiazepine receptors that might be linked to changes in conformantial state of this membrane-bound complex and could partially explain diabetes-induced impairments of GABAergic transmission evaluated in the present study. Our study suggests that nicotinamide and especially GABA play an important role in improving the functioning of brain GABA-benzodiazepine complex impaired in diabetes through specific ligand-mediated mechanism and can be useful in the management of diabetes-associated brain failures.
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PMID:[State of GABA-benzodiazepine receptor complex in diabetic neuropathy: effect of nicotinamide and nicotinoyl-GABA]. 1457 76

The roles of glial energetics and of the glutamine cycle in diabetic encephalopathy have been investigated ex vivo by (13)C NMR in extracts of adult rat brain. Streptozotocin-induced diabetic or euglycemic animals received intravenous infusions of (1-(13)C) glucose in the absence and presence of trifluoroacetic acid or methionine sulfoximine, two selective inhibitors of the glial tricarboxylic acid cycle or of glutamine synthase, respectively. (1-(13)C) glucose infusions resulted in smaller (13)C incorporation in all carbons of cerebral glutamate, glutamine and GABA in the diabetic animals. Co-infusion of trifluoroacetic acid with (1-(13)C) glucose further reduced the (13)C enrichments in cerebral glutamate and glutamine, the decrease being larger in the diabetic animals than in the corresponding euglycemic controls. Methionine sulfoximine decreased to undetectable levels the fractional (13)C enrichment in the carbons of cerebral glutamine in both groups and had no significant effect on (13)C incorporation in glutamate and GABA, suggesting that glutamine is not the main precursor of glutamate and GABA. Additional animals were infused with (1,2-(13)C(2)) acetate, a major substrate of glial metabolism. In this case, (1,2-(13)C(2)) acetate infusions resulted in increased (13)C incorporation in all carbons of glutamate, glutamine and GABA in the diabetic animals. Together, these results reveal that diabetic encephalopathy has an important effect in astroglial metabolism, decreasing glucose transport and metabolism and increasing the relative contribution of glial oxidative metabolism to the support of glutamatergic and GABAergic neurotransmissions.
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PMID:Role of glial metabolism in diabetic encephalopathy as detected by high resolution 13C NMR. 1467 6

Hypoxia causes dysfunction of excitatory and inhibitory neurotransmission, often resulting in encephalopathy, seizures or myoclonus. We evaluated the effects of hypoxia on GABAA receptor (GABAAR) function and expression in an in vitro model of neuronal hypoxia. NT2-N cells, derived from the human NT2 teratocarcinoma cell line, were exposed to < or =1% O2 for 8 h and then used immediately for experiments or allowed to recover under normoxic conditions (95% air/5% CO2) for 24, 48 or 96 h. Hypoxic treatment did not cause obvious morphological changes or cell death. In whole-cell patch-clamp recordings, the GABA current EC50 was unchanged, however, maximal GABA-evoked currents changed in a biphasic manner. Maximal GABA currents were significantly increased immediately after hypoxia, but were significantly reduced after 48 h normoxic recovery, and then returned to baseline after 96 h recovery. Maximal potentiation of 10 microM GABA currents by diazepam was increased 48 h after hypoxia, but potentiation by zolpidem was decreased. Barbiturate enhancement and zinc inhibition of GABA currents were unchanged. Semiquantitative reverse transcriptase (RT)-PCR showed decreased alpha1, alpha5, beta2 and gamma2 subunit mRNA after hypoxia. Hypoxic exposure altered GABAAR physiology and subunit mRNA expression, which may correlate with symptoms observed after hypoxia in vivo.
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PMID:Hypoxia alters GABAA receptor function and subunit expression in NT2-N neurons. 1497 87


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