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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In experimental hepatic encephalopathy and hyperammonemia, extracellular levels of glutamate are increased in hippocampus and cerebral cortex. It has been suggested that overstimulation of glutamate receptors causes a pathological entry of calcium into neurons via receptor-operated (NMDA- and AMPA-type) or voltage-dependent calcium channels leading to calcium overload and cell death. Neurodegeneration as a result of exposure to excitotoxins, including glutamate, can be localized and quantified using 45CaCl2 autoradiography. This approach was used to study cerebral calcium accumulation in rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced in 6 rabbits, acute hyperammonemia in 4 rabbits; 4 control rabbits received sodium-potassium-acetate. At the start of the experiment 500 microCi 45CaCl2 was given intravenously. After development of severe encephalopathy, the animals were killed by decapitation. All rabbits with acute liver failure or acute hyperammonemia developed severe encephalopathy, after 13.2 +/- 1.7 and 19.3 +/- 0.5 hours respectively (mean +/- SEM). Plasma ammonia levels were 425 +/- 46 and 883 +/- 21 mumol/l, respectively (p < 0.05). Control rabbits maintained normal plasma ammonia levels (13 +/- 5 mumol/l), demonstrated normal behaviour throughout the study and were sacrificed after 16 hours. 45Ca(2+)-autoradiograms of 40 microns brain sections were analyzed semiquantitatively using relative optical density and computerized image analysis. As compared to background levels 45Ca was not increased in hippocampus or any other brain area of rabbits with severe encephalopathy from acute liver failure or acute hyperammonemia. This suggests that, despite increased extracellular brain glutamate levels in these conditions, glutamate neurotoxicity was not important for the development of encephalopathy in these rabbits.
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PMID:45CaCl2 autoradiography in brain from rabbits with encephalopathy from acute liver failure or acute hyperammonemia. 807 63

To demonstrate the role of vitamin E on cerebellar function, studies on rabbits fed low and high levels of dietary vitamin E were performed. The L-[3H]glutamate binding to cerebellar membranes of rabbits fed normal, high and low vitamin E diet showed receptor density (Bmax) values (mean +/- SEM) of 274 +/- 13, 637 +/- 37, and 265 +/- 60 pmol/mg protein, respectively, and dissociation equilibrium constant (KD) values of 257 +/- 99, 233 +/- 77, and 120 +/- 15 nM, respectively. Significant difference of Bmax from control was observed in the high dietary vitamin E group and of KD from control for the low dietary vitamin E group. These results indicate that dietary vitamin E levels have demonstrable effects on the central nervous system, especially the glutamate neurotransmitter system in rabbit cerebellum.
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PMID:Effect of dietary vitamin E on L-[3H]glutamate binding in rabbit cerebellum. 809 8

Malate has a number of key roles in the brain, including its function as a tricarboxylic acid (TCA) cycle intermediate, and as a participant in the malate-aspartate shuttle. In addition, malate is converted to pyruvate and CO2 via malic enzyme and may participate in metabolic trafficking between astrocytes and neurons. We have previously demonstrated that malate is metabolized in at least two compartments of TCA cycle activity in astrocytes. Since malic enzyme contributes to the overall regulation of malate metabolism, we determined the activity and kinetics of the mitochondrial and cytosolic forms of this enzyme from cultured astrocytes. Malic enzyme activity measured at 37 degrees C in the presence of 0.5 mM malate was 4.15 +/- 0.47 and 11.61 +/- 0.98 nmol/min/mg protein, in mitochondria and cytosol, respectively (mean +/- SEM, n = 18-19). Malic enzyme activity was also measured in the presence of several endogenous compounds, which have been shown to alter intracellular malate metabolism in astrocytes, to determine if these compounds affected malic enzyme activity. Lactate inhibited cytosolic malic enzyme by a noncompetitive mechanism, but had no effect on the mitochondrial enzyme. alpha-Ketoglutarate inhibited both cytosolic and mitochondrial malic enzymes by a partial noncompetitive mechanism. Citrate inhibited cytosolic malic enzyme competitively and inhibited mitochondrial malic enzyme noncompetitively at low concentrations of malate, but competitively at high concentrations of malate. Both glutamate and aspartate decreased the activity of mitochondrial malic enzyme, but also increased the affinity of the enzyme for malate. The results demonstrate that mitochondrial and cytosolic malic enzymes have different kinetic parameters and are regulated differently by endogenous compounds previously shown to alter malate metabolism in astrocytes. We propose that malic enzyme in brain has an important role in the complete oxidation of anaplerotic compounds for energy.
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PMID:Regulation of mitochondrial and cytosolic malic enzymes from cultured rat brain astrocytes. 878 13

Modulatory actions of Zn2+ (0.05-2 mM) on spontaneous, stimulus evoked excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) and GABA, L-glutamate induced depolarizations were examined in current- and voltage-clamp conditions. Identified and unidentified Helix pomatia L. neurons were used in the experiments. Zn2+ increased the frequency of the spontaneous EPSPs or EPSCs in a dose-dependent manner but the excitation slowly declined with time. Two phasic effects of Zn2+ on stimulus evoked EPSPs or EPSCs were characteristic in both normal and low Ca(2+)-high Mg2+ salines. Zn2+ in a low dose (0.05-0.4 mM) increased, but in a higher dose decreased the amplitude of the evoked EPSP or EPSCs. Higher than 1 mM Zn2+ sustained the voltage dependence of the stimulus evoked EPSPs or EPSCs. Sodium-potassium dependent depolarizations of GABA and glutamate responses were attenuated by zinc ions. The zinc ion sensitivity of neurons derived from active animals was higher then of hibernating species (IC50 = 0.73 +/- 0.006; 1.33 +/- 0.12, respectively, mean +/- SEM, n = 12). We conclude that zinc ions have both pre- and post-synaptic effects. Zinc induced actions on Helix neuronal synapses based on the modulation of a complex phenomenon appear to be more than one mechanism.
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PMID:Actions of Zn2+ on spontaneous, stimulus and transmitter evoked events in Helix neurons. 885 14

Increased glutamate utilization is a part of the metabolic adaptation to oxygen deprivation by the heart. The effect of low-dose L-glutamate (2 mmol/L) during continuous reperfusion after aortic unclamping on postcardioplegic recovery was studied in pig hearts similar in size, anatomy, and function to the human adult heart. After cold crystalloid cardioplegic arrest (CCC) with Bretschneider solution no 3, hearts were excised from pigs weighing 70-80 kgs (heart weight, average +/- SEM: 308 +/- 4 grams), and reperfused in an isolated blood-perfused heart model for 120 minutes. Three groups of hearts were compared. One group of hearts was subjected to 30 minutes of CCC only (30 min group; n = 9), another group of hearts to 90 minutes of CCC and storage (Control group: n = 16), and a third group to 90 minutes of CCC and storage, but with L-glutamate added to the blood reperfusate (2 mmol/L) (Glutamate group: n = 18). In the Control group 14 of 16 hearts (88%) needed electrical defibrillation after start of reperfusion, significantly more (p < 0.05) than the 8 of 18 (44%) in the Glutamate group; the difference between the 30-min (2 of 9 [22%]) and the Glutamate group was not significant (p = 0.48). Developed left-ventricular pressure (DLVP) and positive dP/dtmax (+dP/dtmax) was significantly higher in the Glutamate group than in the Control group during early reperfusion (DLVP: p < 0.05: +dP/dtmax: p < 0.01) and the entire reperfusion (DLVP and +dP/dtmax: p < 0.05), while reperfusion responses in the Glutamate and 30-min groups were not significantly different. Furthermore, myocardial oxygen uptake was significantly higher in the Glutamate group than in the Control group (p < 0.001), but not higher than that in the 30-min group. Decreased lactate release was found in the Glutamate group compared to the Control group during early reperfusion (p < 0.01), and the entire reperfusion (p < 0.001). No differences were found between the Control and Glutamate groups in alanine exchange. Thus, L-glutamate has a beneficial effect in pig hearts on both functional and metabolic recovery after cold crystalloid cardioplegia and storage when present in a concentration even as low as 2 mmol/L during continuous reperfusion after aortic unclamping. A possible mechanism is a glutamate-induced stimulation of the malate-aspartate shuttle leading to increased intramyocardial lactate utilization.
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PMID:Improved recovery after cold crystalloid cardioplegia using low-dose glutamate enrichment during reperfusion after aortic unclamping: a study in isolated blood-perfused pig hearts. 885 93

We have compared the effects of parallel fiber stimuli on extracellularly recorded neurons showing regular or bursting spontaneous activity patterns in the dorsal cochlear nucleus of rat brainstem slices. Ninety percent of regular neurons failed to respond to stimulus currents (1.4 +/- 0.28 mA, mean +/- SEM) significantly greater than those (0.4 +/- 0.07 mA) that elicited responses from 96% of bursting neurons. Responses of bursting neurons were elicited from widely separated loci along the molecular layer. Kynurenic acid and CNQX or DNQX blocked both spontaneous firing and responses to parallel fiber stimuli of bursting neurons. The same agents also blocked responses of regular neurons but had little or no effect on their spontaneous firing rates. AP-5 caused small decreases in spontaneous rates of both bursting and regular neurons but did not appear to affect responses to stimuli. The data support the hypothesis that the responses of both regular and bursting neurons to parallel fiber stimulation are mediated by glutamate, acting mainly through non-NMDA receptors. Spontaneous activity of bursting, but not regular, neurons also requires non-NMDA glutamatergic transmission, suggesting that the spontaneous firing of bursting neurons, consisting largely of cartwheel cells, may depend upon granule cell activity.
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PMID:Effects of parallel fiber stimulation on neurons of rat dorsal cochlear nucleus. 888 Jan 91

Rotating disk electrode (RDE) voltammetry was used to examine the effect of N-methyl-D-aspartate (NMDA) on the initial velocity of dopamine (DA) uptake in suspensions of rat striatal tissue. Transport velocities were determined by measuring the rate of clearance of 2 microM DA added to the tissue suspension. NMDA (200 microM) was found to increase the initial velocity of DA transport from 548 +/- 28 to 803 +/- 63 pmol/s per g tissue (mean +/- SEM; P < 0.005). The increase was reversed by the competitive NMDA antagonist AP5, and thus appears to be receptor-mediated. In a separate experiment, lower concentrations of NMDA (20-100 microM) yielded a high correlation (r = 0.96; P < 0.05) of velocity versus concentration. Kainic acid (10 microM) also was found to increase the initial rate of uptake, from 505 +/- 34 to 702 +/- 71 pmol/s per g (P < 0.05). The results of this study indicate that the rate of DA uptake in the striatum can be modulated in vitro by presynaptic ionotropic glutamate receptors.
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PMID:Regulation of dopamine uptake in rat striatal tissue by NMDA receptors as measured using rotating disk electrode voltammetry. 891 3

The anticonvulsive drug, valproic acid (VPA), inhibits the biosynthesis of carnitine, and may contribute in this way to carnitine deficiency associated with VPA therapy. The conversion of [3H]-butyrobetaine into [3H]-carnitine was determined 60 min following a single intraperitoneal (i.p.) dose of 1.2 mmol/kg VPA in rats. The fraction of radioactivity found in [3H]-carnitine in the liver decreased from 63.2 +/- 1.50% to 39.2 +/- 1.11% (mean +/- SEM). Total carnitine in the liver also decreased, whereas the precursor butyrobetaine increased from 5.01 +/- 0.71 nmol/g to 8.22 +/- 0.82 nmol/g (mean +/- SEM). VPA also exhibited a dramatic effect on the conversion of an unlabeled loading amount of butyrobetaine. The increment in total carnitine caused by butyrobetaine in liver was reduced from 161 +/- 15.4 nmol/g to 53.2 +/- 5.11 nmol/g (mean +/- SEM). These data prove that VPA reduces the flux through butyrobetaine hydroxylase (EC 1.14.11.1.). The drug in vitro, however, did not inhibit the enzyme directly. Searching for the mechanism of action, we found that VPA decreased the level of alpha-ketoglutarate (alpha-KG; a cofactor of butyrobetaine hydroxylase) from 73.5 +/- 2.90 nmol/g to 52.9 +/- 2.2 nmol/g (mean +/- SEM) in the liver. The level of 1-glutamate showed a rather dramatic decrease in the liver. Moreover, alpha-KG proved to have a protective role against VPA in the [3H]-butyrobetaine conversion experiment.
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PMID:Inhibition of carnitine biosynthesis by valproic acid in rats--the biochemical mechanism of inhibition. 893 54

We have examined the effects of a range of opioid receptor subtype selective agonists on K+ evoked glutamate release from perfused rat cerebrocortical slices. Dual application (S1 and S2) of K+ (46 mM) evoked dual monophasic glutamate release profiles. When areas under the release curves were calculated an S2/S1 ratio for control slices of 1.07 +/- 0.08 (n = 75) was obtained, this was reduced by 80% with EGTA (0.1 mM) treatment confirming the presence of a Ca2+ regulated release process, Morphine produced a dose-dependent inhibition of the S2/S1 ratio. At 1 microM this amounted to 78 +/- 12% (mean +/- SEM; n = 6). (D-Ala2,MePhe4,gly(ol)5)enkephalin (DAMGO; 60 +/- 12%, n = 6 at 1 microM), and spiradoline (53 +/- 14% at 1 and 71 +/- 11% at 100 microM, both n = 6) also inhibited glutamate release in a cyprodime (10 microM) and norbinaltorphimine (10 microM) reversible manner. (D-Pen2.5) enkephalin (DPDPE; 1 microM) was ineffective. All agents tested did not affect basal glutamate release. Collectively these data implicate a role for mu and kappa opioids in the control of evoked glutamate release and their potential for neuroprotective therapy.
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PMID:mu- and kappa-opioids inhibit K+ evoked glutamate release from rat cerebrocortical slices. 894 32

Benzoic acid metabolism, which is primarily a function of liver mitochondria, depending on the concentration of adenosine triphosphate (ATP), coenzyme A (CoA), and glycine in the mitochondrial matrix, was investigated in both rats with long-term cholestasis caused by bile duct ligation (BDL) and sham-operated control rats. In isolated liver mitochondria, hippurate production from benzoate in the presence of saturating glycine concentrations was reduced in BDL rats by 36% with L-glutamate as a source for ATP, by 21% in the presence of succinate, and by 31% in the presence of ATP plus oligomycine. This reduction in benzoate metabolism is in the same range as the previously observed reduction in the activity of the electron transport chain in liver mitochondria from BDL rats. The mitochondrial CoA pool, which can be rate-limiting for benzoic acid metabolism, was not different between BDL and control rats. The activity of benzoyl-CoA synthase, the enzyme catalyzing the rate-limiting step in benzoate metabolism, was reduced by 25%, and the activity of benzoyl-CoA:glycine N-transferase was reduced by 66% in BDL rats. The activity of benzoyl-CoA synthase was significantly inhibited by lithocholate, suggesting that hepatic accumulation of hydrophobic bile acids could contribute to the observed reduction of benzoate metabolism in BDL rats. Benzoate metabolism was also studied in vivo by monitoring the urinary hippurate excretion after intraperitoneal administration of benzoate (100 micromol/100 g of body weight). The time course of hippurate excretion was not different between BDL and control rats. Hippurate excretion over 24 hours after benzoate administration averaged 89.7 +/- 4.0% of the administered dose in BDL and 74.4 +/- 6.9% (mean +/- SEM, difference not significant) in control rats. This finding could be explained by an increase in mitochondrial protein in BDL rats, averaging 2.34 +/- 0.29 g per liver in BDL and 1.35 +/- 0.07 g per liver in control rats (mean +/- SEM, p < .05). Thus, the studies show that benzoate metabolism reflects mitochondrial function in BDL rats both in vivo and in vitro, and that mitochondrial proliferation compensates for the observed decrease in benzoic acid metabolism in isolated mitochondria in vitro.
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PMID:Benzoic acid metabolism reflects hepatic mitochondrial function in rats with long-term extrahepatic cholestasis. 902 34


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