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

Na+/K+-ATPase activity and GABA uptake were measured in the bulk isolated astrocytes and synaptosomes from rats in which an early, metabolic phase of hepatogenic encephalopathy (HE) was induced by the treatment with thioacetamide (TAA). Both the enzyme activity and the amino acid neurotransmitter uptake were increased above control in the astroglial fraction but remained unaffected in synaptosomes. The results lend support to the earlier observations that the astrocytes are the primary target cells in HE. Furthermore, they may be interpreted as indicating that the early astroglial reaction to HE comprises stimulation of the astrocytes' function, especially concerning clearance of K+ ions and neurotransmitters from the extracellular space of CNS.
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PMID:Na+/K+-ATPase activity and GABA uptake in astroglial cell-enriched fractions and synaptosomes derived from rats in the early stage of experimental hepatogenic encephalopathy. 299 45

Previously we have shown that sera from patients with fulminant hepatic failure (FHF) will inhibit partially purified rat brain Na+, K+-ATPase and sodium efflux from human leucocytes in vitro. Similar inhibition may be involved in the pathogenesis of encephalopathy and cerebral oedema in these patients. In the present study we have attempted to establish whether the activity of brain Na+, K+-ATPase is decreased in vivo in rats with D-galactosamine induced hepatic failure using homogenates of snap-frozen brains. Na+, K+-ATPase activity was significantly reduced in the forebrain region at the stage of mild encephalopathy (43 h after injection), while at the deeper stage of coma (43-53 h after injection) enzyme activity was further reduced in the forebrain region and was also significantly reduced in the hindbrain region. Ouabain insensitive ATPase activity was not significantly altered at any time. While a significant increase in the water content (0.5%) of the hindbrain region was found 43 h after galactosamine, there was no clear correlation between the development of cerebral oedema and the reduction of Na+, K+-ATPase activity. The activity of partially purified normal rat brain Na+, K+-ATPase was 15% lower when incubated with sera from rats in the deep stage of coma compared with control sera. These data support other evidence that the reduction in brain Na+, K+-ATPase is likely to be due to toxic substance circulating in serum which have been shown to inhibit this enzyme in vitro and to cause coma when administered to normal animals.
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PMID:Reduced brain Na+, K+-ATPase activity in rats with galactosamine-induced hepatic failure: relationship to encephalopathy and cerebral oedema. 302

Sera from patients with fulminant hepatic failure (FHF) has previously been shown to contain substance(s) which inhibit leucocyte ouabain-sensitive sodium efflux and rat brain Na+, K+-dependent ATPase in vitro. Similar effects in the patients could be an important mechanism in the development of encephalopathy and cerebral oedema. In previous studies, bilirubin, free fatty acids and mercaptans have been shown to inhibit Na+, K+-ATPase in vitro. The present report is concerned with the effects of a number of other potentially toxic substances present in the serum of patients with FHF. Chenodeoxycholic acid, p-hydroxyphenyllactic acid, p-hydroxyphenylpyruvic acid and endotoxin caused 30-45% inhibition of partially purified rat brain Na+, K+-ATPase at concentrations known to occur in the serum of patients with FHF. At low concentrations the inhibitory effects of these substances were additive, but at higher concentrations a maximum level of inhibition was reached. These further substances are likely, therefore, to be of importance in the disturbances of brain function found in FHF.
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PMID:Inhibition of partially purified rat brain Na+, K+-dependent ATPase by bile acids, phenolic acids and endotoxin. 632 Oct 86

Previous studies have demonstrated abnormalities of intracellular electrolyte content and sodium transport in leukocytes of patients with fulminant hepatic failure. The current study was undertaken to establish whether similar abnormalities were present in patients with encephalopathy from advanced cirrhosis. Results from 19 patients with advanced cirrhosis showed values for the leukocyte total sodium efflux-rate constant were significantly reduced in patients, 3.02 +/- 1 SEM 0.12 h-1, compared to control values, 3.80 +/- 0.06 h-1. This reduction was due primarily to a lowering of the ouabain-sensitive component of sodium efflux, a measure of Na,K-ATPase activity. In comparison, leukocytes from patients with fulminant hepatic failure show a greater inhibition of the ouabain-sensitive component of sodium efflux with a raised ouabain-insensitive efflux. Although cirrhosis has generally been associated with potassium depletion, the intracellular potassium content of the cirrhotic patients' leukocytes was normal. Since the leukocyte is considered to be a good cell model and because abnormalities of sodium transport have been shown in the leukocytes of these patients, it is likely that similar abnormalities of sodium transport are present in other organs, including the brain.
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PMID:Abnormalities in the leukocyte sodium pump in advanced cirrhosis. 726 13

Endogenous digitalis-like factor (EDLF), an inhibitor of membrane Na+/K(+)-ATPase, is discussed to be involved in the pathogenesis of cirrhogenic portal hypertension, ascites formation and development of functional hepatorenal failure. Therefore, we investigated the serum content of this mediator in patients with liver cirrhosis Child-Pugh stage A, B, and C (n = 27) by means of enzyme immunoassay with a specific digoxin antibody. Furthermore, a correlation analysis was performed in order to find out correlations between signs of cell injury, cholestasis, synthetic cell function, ascites formation, and hepatorenal failure. Our results demonstrate that EDLF is significantly elevated in Child C cirrhosis (0.61 +/- 0.15 ng/ml) in comparison to Child A cirrhosis (0.013 +/- 0.2 ng/ml) and is also higher than in Child B cirrhosis (0.23 +/- 0.25 ng/ml). In patients without ascites EDLF (0.056 +/- 0.19 ng/ml) differs significantly from that of patients with non-complicated ascites (0.156 +/- 0.176 ng/ml) and from that of patients with therapy refractory ascites (0.66 +/- 0.17 ng/ml) or hepatorenal failure (1.56 ng/ml). There are no correlations between EDLF and renal function. Significant correlations were demonstrated for cholestasis (serum bilirubin), synthesis function (serum protein, Quick's value, cholinesterase, fibrinogen, albumin), and the degree of portasystemic encephalopathy (number connection test). We conclude that EDLF may act as a mediator in the process of progressive portal hypertension and its complications due to cirrhosis. This process of progression is caused by the inhibition of Na+/K(+)-ATPase, vasoconstriction, and endothelin secretion.
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PMID:[Endogenous digitalis-like factor in liver cirrhosis and cholestasis]. 748 6

The mitochondrial ATPase 6 gene encodes a subunit of F1F0 adenosine triphosphate (ATP) synthase. A mutation in the ATPase 6 gene has been genetically linked to two maternally inherited genetic diseases: neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP) and certain cases of subacute necrotizing encephalopathy (SNE). Although the severity of both NARP and SNE disease were correlated with the quantity of the ATPase 6leu156-->arg mutation in each patient, the mutation could not be shown to alter F1F0-ATP synthase activity. To investigate the biochemical effects of the ATPase 6leu156-->arg mutation on F1F0-ATP synthase, the aleu207-->arg mutation was constructed in the F1F0-ATP synthase from Escherichia coli to serve as a model for the disease mutation. Characterization of the model bacterial enzyme revealed that the mutation abolishes detectable ATP synthesis via oxidative phosphorylation. The aleu207-->arg mutation results in a structural perturbation blocking proton translocation through F1F0-ATP synthase. The results suggest that a structural defect in human F1F0-ATP synthase is the biochemical basis for NARP and SNE.
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PMID:The aleu207-->arg mutation in F1F0-ATP synthase from Escherichia coli. A model for human mitochondrial disease. 850 61

Mutations in the tRNA genes of mitochondrial DNA (mtDNA) cause the debilitating MELAS (mitochondrial, myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibres) syndromes. These mtDNA mutations affect respiratory chain function, apparently without decreasing cellular ATP concentration [Moudy et al. (1995) PNAS, 92, 729-733]. To address this issue, we investigated the role of mitochondrial ATP synthesis in fibroblasts from MELAS and MERRF patients. The maximum rate of mitochondrial ATP synthesis was decreased by 60-88%, as a consequence of the decrease in the proton electrochemical potential gradient of MELAS and MERRF mitochondria. However, in quiescent fibroblasts neither ATP concentration or the ATP/ADP ratio was affected by the lowered rate of ATP synthesis. We hypothesized that the low ATP demand of quiescent fibroblasts masked the mitochondrial ATP synthesis defect and that this defect might become apparent during higher ATP use. To test this we simulated high energy demand by titrating cells with gramicidin, an ionophore that stimulates ATP hydrolysis by the plasma membrane Na+/K+-ATPase. We found a threshold gramicidin concentration in control cells at which both the ATP/ADP ratio and the plasma membrane potential decreased dramatically, due to ATP demand by the Na+/K+-ATPase outstripping mitochondrial ATP synthesis. In MELAS and MERRF fibroblasts the corresponding threshold concentrations of gramicidin were 2-20-fold lower than those for control cells. This is the first demonstration that cells containing mtDNA mutations are particularly sensitive to increased ATP demand and this has several implications for how mitochondrial dysfunction contributes to disease pathophysiology. In particular, the increased susceptibility to plasma membrane depolarization will render neurons with dysfunctional mitochondria susceptible to excitotoxic cell death.
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PMID:Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. 991 28

Darier's disease (DD) is a rare, dominantly inherited disorder that affects the skin producing a variety of types of lesion. Close examination of lesional DD skin shows the presence of abnormal keratinization (epidermal differentiation) and acantholysis (loss of cohesion) of keratinocytes. A number of clinical studies have described the co-occurrence of various neurological and psychiatric symptoms with DD, including mood disorders, epilepsy, mental retardation and a slowly progressive encephalopathy. A single locus for DD has been mapped to chromosome 12q23-q24.1, and a variety of missense, nonsense, frameshift and splicing mutations in the ATP2A2 gene have been described recently in families with DD. This gene encodes the sarcoplasmic/endoplasmic reticulum calcium-pumping ATPase SERCA2, which has a central role in intra-cellular calcium signalling. In this study, we performed mutation analysis on ATP2A2 in 19 unrelated DD patients, of whom 10 had neuropsychiatric phenotypes. We identified and verified 17 novel mutations predicting conservative and non-conservative amino acid changes, potential premature translation terminations and potential altered splicing. Our findings confirm that mutations in ATP2A2 are associated with DD. In neuropsychiatric cases, there was a non-random clustering of mutations in the 3' end of the gene ( P = 0.01), and a predominance of the missense type (70% versus 38% in DD patients). This supports the hypothesis that the DD gene has pleiotropic effects in brain and that mutations in SERCA2 are implicated in the pathogenesis of neuropsychiatric disorders.
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PMID:ATP2A2 mutations in Darier's disease and their relationship to neuropsychiatric phenotypes. 1044 25

This study was done to determine the effects of hyperglycemia or hypoglycemia on brain cell membrane function and energy metabolism during the immediate reoxygenation-reperfusion period after hypoxia-ischemia (HI). Forty-five newborn piglets were divided randomly into four experimental groups: normoxia control (NC, n=9); HI/reoxygenation-reperfusion (RR) control (HC, n=11); HI/RR hyperglycemia (HE, n=12); and HI/RR hypoglycemia (HO, n=13) group. Animals were subjected to transient HI for 30 min followed by 2 h of RR. Cerebral HI was induced by temporary but complete occlusion of bilateral common carotid arteries with surgical clips and simultaneous breathing with 8% oxygen. Glucose was unregulated in HC group, and controlled by modified glucose clamp technique immediately after HI in HE (350 mg/dl) and HO (50 mg/dl) groups. During HI, heart rate, base deficit, glucose and lactate level in the blood and cerebrospinal fluid increased, and arterial pH, oxygen saturation and blood pressure decreased significantly in HC, HE and HO groups. During RR, these abnormalities returned to normal values, but lactic acidosis persisted especially in HO group. Cerebral Na(+),K(+)-ATPase activity decreased, and lipid peroxidation products increased significantly in HC group than in NC group, and these abnormalities were significantly aggravated in HE, but not in HO, group. Brain ATP and phosphocreatine levels in HE group were significantly reduced compared to the corresponding values in NC, HC and HO groups. In summary, hyperglycemia, but not hypoglycemia immediately after HI interfered with the recovery of brain cell membrane function and energy metabolism. These findings suggest that post-hypoxic-ischemic hyperglycemia is not beneficial and might even be harmful in neonatal hypoxic-ischemic encephalopathy.
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PMID:Effects of hyperglycemia or hypoglycemia on brain cell membrane function and energy metabolism during the immediate reoxygenation-reperfusion period after acute transient global hypoxia-ischemia in the newborn piglet. 1136 56

Dysfunction of mitochondrial ATPase (F1F(o)-ATP synthase) due to missense mutations in ATP6 [mtDNA (mitochondrial DNA)-encoded subunit a] is a frequent cause of severe mitochondrial encephalomyopathies. We have investigated a rare mtDNA mutation, i.e. a 2 bp deletion of TA at positions 9205 and 9206 (9205DeltaTA), which affects the STOP codon of the ATP6 gene and the cleavage site between the RNAs for ATP6 and COX3 (cytochrome c oxidase 3). The mutation was present at increasing load in a three-generation family (in blood: 16%/82%/>98%). In the affected boy with severe encephalopathy, a homoplasmic mutation was present in blood, fibroblasts and muscle. The fibroblasts from the patient showed normal aurovertin-sensitive ATPase hydrolytic activity, a 70% decrease in ATP synthesis and an 85% decrease in COX activity. ADP-stimulated respiration and the ADP-induced decrease in the mitochondrial membrane potential at state 4 were decreased by 50%. The content of subunit a was decreased 10-fold compared with other ATPase subunits, and [35S]-methionine labelling showed a 9-fold decrease in subunit a biosynthesis. The content of COX subunits 1, 4 and 6c was decreased by 30-60%. Northern Blot and quantitative real-time reverse transcription-PCR analysis further demonstrated that the primary ATP6--COX3 transcript is cleaved to the ATP6 and COX3 mRNAs 2-3-fold less efficiently. Structural studies by Blue-Native and two-dimensional electrophoresis revealed an altered pattern of COX assembly and instability of the ATPase complex, which dissociated into subcomplexes. The results indicate that the 9205DeltaTA mutation prevents the synthesis of ATPase subunit a, and causes the formation of incomplete ATPase complexes that are capable of ATP hydrolysis but not ATP synthesis. The mutation also affects the biogenesis of COX, which is present in a decreased amount in cells from affected individuals.
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PMID:Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 2 bp microdeletion of TA at positions 9205 and 9206. 1526 3


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