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C R Murthy

Publications and source records attributed to C R Murthy.

At least 37 records · Page 2Linked to original sources
PubMed1991

Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes.

Binding of glutamate and muscimol (an agonist for GABAA receptors) to their respective receptors has been studied in the cerebellum of normal and hyperammonemic rats. There was a decrease in both high- and low-affinity binding of glutamate in the cerebellum during hyperammonemia. Kinetic studies revealed that the decrease is due to a reduction in the number of binding sites, but not due to changes in the binding affinities. Further studies also revealed that the decrease was only in the N-methyl-D-aspartate (NMDA)-specific binding sites without any alterations in the binding to non-NMDA sites represented by kianic acid (KA)- and quisqualic acid (QQ)-sensitive receptor sites. These effects were also mimicked when the membrane preparations from the cerebellum of normal animals were incubated with ammonium acetate. Enhancement of muscimol binding was observed in animals injected with ammonium acetate. It is concluded that hyperammonemic states, even in the presence of a functional liver, are capable of altering amino acid neurotransmission and this might play an important role in cerebral dysfunction under these conditions.

Ammonia↗
PubMed1991

Hyperammonemic alterations in the uptake and release of glutamate and aspartate by rat cerebellar preparations.

Release and uptake of neurotransmitter amino acids, glutamate and aspartate, were studied in the synaptosomes, astrocytes and in the perikarya of granule neurons isolated from the cerebella of normal and hyperammonemic rats. During acute hyperammonemia, depolarization-induced release of both the amino acids from the synaptosomes was elevated. The Vmax values of high-affinity uptake systems were elevated without alterations in the Km values for these two amino acids during acute hyperammonemic states. In the case of the low-affinity uptake system of these two amino acids, there was a decrease in the Km values without alterations in the Vmax values. These results are discussed in relation to the mechanism of ammonia toxicity.

Ammonia↗
PubMed1991

Variations in the effects of L-methionine-DL-sulfoximine on the activity of cerebral gamma-glutamyl transpeptidase in rats as a function of age.

Changes in the activity of gamma-glutamyl transpeptidase (GGTP) and the effects of a subacute dose (150 mg/kg b.wt.) of methionine sulfoximine (MSO) on its activity were studied in cerebral cortex, cerebellum and brainstem of rats of 4 different age groups. GGTP activity increased with increasing age between days 10 and 180 after birth and decreased between 180 and 360 days of age in these 3 regions of the brain. Older animals showed convulsions and succumbed to the toxic effects of MSO. In the younger animals, wobbly gait and splayed leggedness were noticed in the earlier time periods and these animals recovered from the toxic effects of the drug. Following the administration of MSO, GGTP activity was suppressed in all the regions (excepting the cerebral cortex and cerebellum of 90-day-old animals). In 10- and 90-day-old animals). In 10- and 90-day-old animals, there was a complete recovery of enzyme activity which exceeded the control value as the time progressed. No such recovery was observed in 180- and 360-days-old animals. Parallel changes were observed in the GGTP activity and the behavioural pattern of the animals. These results were discussed in relation to the localization of this enzyme in astrocytes and capillaries.

Aging↗
PubMed1990

Effect of methionine sulfoximine on pyruvate dehydrogenase, citric acid cycle enzymes and aminotransferases in the subcellular fractions isolated from rat cerebral cortex.

The effect of acute and subacute doses of L-methionine-DL-sulfoximine (MSI) were studied on the activities of pyruvate dehydrogenase, enzymes of citric acid cycle and aspartate and alanine aminotransferases in the mitochondria, synaptosomes and cytosol of rat brain. In general, the activities of pyruvate dehydrogenase and of the citric acid cycle enzymes, except malate dehydrogenase (malate----oxaloacetate), were elevated in all 3 subcellular fractions. Malate dehydrogenase activity (malate----oxaloacetate) was suppressed in the mitochondria while the activity of this enzyme in the reverse direction was enhanced in the cytosol. Activities of aspartate and alanine aminotransferases were suppressed under these conditions. As the effects of MSI on these enzymes were similar to those observed upon the administration of ammonium salts, it is suggested that the hyperammonemic state induced by MSI might derange the operation of the malate-aspartate shuttle. Increased activities of citric acid cycle enzymes in the cytosol suggested the existence of a small population of mitochondria which was highly vulnerable either to ammonia or to MSI.

Ammonia↗
PubMed1990

Effects of partial hepatectomy on the enzymes of cerebral glutamate and branched-chain amino acid metabolism.

Cerebral activities of glutamate dehydrogenase (GDH), glutamine synthetase (GS), and branched-chain amino acid aminotransferase (BCAA-T) along with the levels of ammonia in serum and brain were determined in normal, sham-operated and partially hepatectomized rats. Mild hyperammonemia was observed in sham-operated animals, and the cerebral activities of all the enzymes studied were found to be decreased when compared with those of normal animals. In hepatectomized animals, blood and brain ammonia levels were elevated further. In these animals, GS activity returned to the normal values and that of BCCA-T was elevated, while there was a continued suppression of GDH activity. These results were discussed in relation to the utilization of BCAA (leucine, isoleucine, and valine) for the synthesis of glutamate and glutamine in brain in hyperammonemic states.

Amino Acids, Branched-Chain↗
PubMed1990

Pulse rate, pre-competition tension and performance in 10,000 meter elite runners of both sexes.

Five male and 3 female runners who participated in 10,000 meter distance run in South Asian Federation (SAF) Games, 1987 were volunteered for this pilot study. The pulse rate at rest, 1 hour prior to competition and post-run for 30 min at 5 min intervals were recorded. It was observed that the runners who showed less rise of pulse prior to competition, performed better. This might be attributed to less pre-competition tension in them which helped the athletes to perform better.

Adult↗
PubMed1989

Activities of pyruvate dehydrogenase, enzymes of citric acid cycle, and aminotransferases in the subcellular fractions of cerebral cortex in normal and hyperammonemic rats.

Activity levels of pyruvate dehydrogenase, enzymes of citric acid cycle, aspartate and alanine aminotransferases were estimated in mitochondria, synaptosomes and cytosol isolated from brains of normal rats and those injected with acute and subacute doses of ammonium acetate. In mitochondria isolated from animals treated with acute dose of ammonium acetate, there was an elevation in the activities of pyruvate, isocitrate and succinate dehydrogenases while the activities of malate dehydrogenase (malate----oxaloacetate), aspartate and alanine aminotransferases were suppressed. In subacute conditions a similar profile of change was noticed excepting that there was an elevation in the activity of alpha-ketoglutarate dehydrogenase in mitochondria. In the synaptosomes isolated from animals administered with acute dose of ammonium acetate, there was an increase in the activities of pyruvate, isocitrate, alpha-ketoglutarate and succinate dehydrogenases while the changes in the activities of malate dehydrogenase, aspartate and alanine amino transferases were suppressed. In the subacute toxicity similar changes were observed in this fraction except that the activity of malate dehydrogenase (oxaloacetate----malate) was enhanced. In the cytosol, pyruvate dehydrogenase and other enzymes of citric acid cycle except malate dehydrogenase were enhanced in both acute and subacute ammonia toxicity though their activities are lesser than that of mitochondria. In this fraction malate dehydrogenase (oxaloacetate----malate) was enhanced while activities of malate dehydrogenase (malate----oxaloacetate), aspartate and alanine aminotransferases were suppressed in both the conditions. Based on these results it is concluded that the decreased activities of malate dehydrogenase (malate----oxaloacetate) in mitochondria and of aspartate aminotransferase in mitochondria and cytosol may be responsible for the disruption of malate-aspartate shuttle in hyperammonemic state.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗
PubMed1989

Differential effects of ammonia and beta-methylene-DL-aspartate on metabolism of glutamate and related amino acids by astrocytes and neurons in primary culture.

The effects of ammonium chloride (3 mM) and beta-methylene-DL-aspartate (BMA; 5 mM) (an inhibitor of aspartate aminotransferase, a key enzyme of the malate-aspartate shuttle (MAS] on the metabolism of glutamate and related amino acids were studied in primary cultures of astrocytes and neurons. Both ammonia and BMA inhibited 14CO2 production from [U-14C]- and [1-14C]glutamate by astrocytes and neurons and their effects were partially additive. Acute treatment of astrocytes with ammonia (but not BMA) increased astrocytic glutamine. Acute treatment of astrocytes with ammonia or BMA decreased astrocytic glutamate and aspartate (both are key components of the MAS). Acute treatment of neurons with ammonia decreased neuronal aspartate and glutamine and did not apparently affect the efflux of aspartate from neurons. However, acute BMA treatment of neurons led to decreased neuronal glutamate and glutamine and apparently reduced the efflux of aspartate and glutamine from neurons. The data are consistent with the notion that both ammonia and BMA may inhibit the MAS although BMA may also directly inhibit cellular glutamate uptake. Additionally, these results also suggest that ammonia and BMA exert differential effects on astroglial and neuronal glutamate metabolism.

Amino Acids↗
PubMed1988

Pyruvate decarboxylation in astrocytes and in neurons in primary cultures in the presence and the absence of ammonia.

Oxidative decarboxylation of [1-14C]pyruvate was studied in primary cultures of neurons and of astrocytes. The rate of this process, which is a measure of carbon flow into the tricarboxylic acid (TCA) cycle and which is inhibited by its end product, acetyl CoA, was determined under conditions which would either elevate or reduce the components of the malate-aspartate shuttle (MAS). Addition of aspartate (1 mM) was found to stimulate pyruvate decarboxylation in astrocytes whereas addition of glutamate (or glutamine) had no effect. Since aspartate is a precursor for extramitochondrial malate, and thus intramitochondrial oxaloacetate, whereas glutamate and glutamine are not, this suggests that an increase in oxaloacetate level stimulates TCA cycle activity. Conversely, a reduction of the glutamate content by 3 mM ammonia, which might reduce exchange between glutamate and aspartate across the mitochondrial membrane, suppressed pyruvate decarboxylation. This effect was abolished by addition of glutamate or glutamine or exposure to methionine sulfoximine (MSO). These findings suggest that impairment of MAS activity by removal of MAS constituents decreases TCA cycle activity whereas replenishment of these compounds restores the activity of the TCA cycle. No corresponding effects were observed in neurons.

Ammonium Chloride↗
PubMed1988

Age-dependent variation in the sensitivity of rat brain glutamine synthetase to L-methionine-DL-sulfoximine.

Effects of a subacute dose (150 mg/kg body wt) of methionine sulfoximine was studied on the behavioural changes and glutamine synthetase activity in cerebral cortex, cerebellum and brain stem of rats of four different age groups. Animals of 10 days and 90 days age groups were less vulnerable to the toxic effects of methionine sulfoximine. Rats of 180 days age exhibited various behavioural changes upon the administration of methionine sulfoximine and entered into convulsions at the end of 17 hr. In rats of 360 days age group these changes appeared quite early and the animals convulsed at the end of 13 hr. Animals of these two age groups failed to recover from toxic effects of methionine sulfoximine. Methionine sulfoximine inhibited glutamine synthetase activity in the brains of rats of all age groups. Maximum inhibition of activity was noticed at the end of 12 hr in 10-day-old rats while in the animals of other age groups it was seen at the end of 3 hr. In animals of all age groups the enzyme activity was inhibited by 60-70% except in 360-day-old rats where the inhibition was 95%. Behavioural changes and inhibition of glutamine synthetase were out of phase with each other. It is suggested that the toxicity of methionine sulfoximine may not be due to its effect on glutamine synthetase alone. Further, these results also suggest that the toxic effects of methionine sulfoximine vary with the age of the animal.

Aging↗
PubMed1988

Branched chain amino acid transaminases in brain in methionine sulphoximine (MSI) toxicity.

The effect of intraperitoneal administration of L-methionine-DL-sulphoximine (MSI) was studied on branched-chain amino acid transaminases (BCAA-T) in different regions of rat brain and in liver. Administration of an acute dose of MSI (300 mg/kg body weight) resulted in a significant decrease in leucine aminotransferase activity in cerebral cortex, cerebellum, and brain-stem, while the activity of isoleucine aminotransferase was enhanced in hippocampus, corpus striatum, brain stem, and midbrain. Activities of both these enzymes changed marginally or remained unaltered in other regions of the brain. Valine aminotransferase showed a significant decrease in all the regions of the brain except in cerebellum. Following the administration of a sub-acute dose of MSI (150 mg/kg body wt.), the activities of the three BCAA aminotransferases were found to be enhanced in all regions of the brain. The results are discussed in relation to the utilization of BCAA for the production of glutamate and glutamine in hyperammonemia.

Animals↗
PubMed1987

Comparison between acute and chronic effects of ammonia on branched-chain amino acid oxidation and incorporation into protein in primary cultures of astrocytes and of neurons.

A comparison was made of acute and chronic effects of ammonia on production of 14CO2 from the [U-14C] labeled branched-chain amino acids (BCAA) leucine, isoleucine, and valine as well as from [1-14C] leucine, and on the incorporation of radioactivity from these amino acids into a perchloric-acid-precipitable protein fraction in astrocytes and neurons in primary cultures. Acute exposure of astrocytes to 3mM ammonium chloride suppressed 14CO2 production from [U-14C] BCAA and especially from [1-14C] leucine. This inhibitory effect was abolished or even reversed [( U-14C] leucine) after chronic exposure to ammonia. Analogously, incorporation of radioactivity into the protein fraction was inhibited after acute exposure but not after chronic exposure of astrocytes to ammonia. The total protein content per culture was increased after chronic exposure. In neurons, production of 14CO2 and incorporation of 14C into proteins were less affected than in astrocytes. These results are discussed in relation to the ability of the two cell types to synthesize glutamine.

Amino Acids, Branched-Chain↗
PubMed1987

Acute effect of ammonia on branched-chain amino acid oxidation and incorporation into proteins in astrocytes and in neurons in primary cultures.

14CO2 production and incorporation of label into proteins from the labeled branched-chain amino acids, leucine, valine, and isoleucine, were determined in primary cultures of neurons and of undifferentiated and differentiated astrocytes from mouse cerebral cortex in the absence and presence of 3 mM ammonium chloride. Production of 14CO2 from [1-14C]leucine and [1-14C]valine was larger than 14CO2 production from [U-14C]leucine and [U-14C]valine in both astrocytes and neurons. In most cases more 14CO2 was produced in astrocytes than in neurons. Incorporation of labeled branched-chain amino acids into proteins varied with the cell type and with the amino acid. Addition of 3 mM ammonium chloride greatly suppressed 14CO2 production from [1-14C]-labeled branched chain amino acids but had little effect on 14CO2 production from [U-14C]-labeled branched-chain amino acids in astrocytes. Ammonium ion, at this concentration, suppressed the incorporation of label from all three branched-chain amino acids into proteins of astrocytes. In contrast, ammonium ion had very little effect on the metabolism (oxidation and incorporation into proteins) of these amino acids in neurons. The possible implications of these findings are discussed, especially regarding whether they signify variations in metabolic fluxes and/or in magnitudes of precursor pools.

Amino Acids, Branched-Chain↗
PubMed1985

Differential response of enzymes of glutamate metabolism in neuronal perikarya and synaptosomes in acute hyperammonemia in rat.

Activity levels of the enzymes of glutamate metabolism were determined in the neuronal perikarya and synaptosomes isolated from the cerebral cortex of normal and hyperammonemic rats. In neuronal perikarya, the activities of glutamate dehydrogenase, aspartate, alanine aminotransferases and glutamine synthetase were elevated in hyperammonemic states. In synaptosomes, glutamate dehydrogenase and aspartate aminotransferase were suppressed, while glutamine synthetase and glutaminase were elevated. These results suggested the involvement of neuronal perikarya in ammonia detoxification at least in acute hyperammonemic states.

Alanine Transaminase↗
PubMed1985

Cerebral citric acid cycle enzymes in methionine sulfoximine toxicity.

The activity levels of pyruvate dehydrogenase, enzymes of the citric acid cycle, aspartate and alanine aminotransferases, and NADP+-isocitrate dehydrogenase were determined in the cerebral cortex, cerebellum, brain stem, corpus striatum, hippocampus, and midbrain regions of normal rats and rats injected with acute and subacute doses of methionine sulfoximine (MSI). In both conditions there was an elevation in the activities of pyruvate dehydrogenase and all the enzymes of the citric acid cycle except malate dehydrogenase, whereas the activities of aminotransferases and NADP+-isocitrate dehydrogenase were suppressed in all the cerebral regions. It is suggested that the operational rates of the citric acid cycle would be enhanced in MSI-induced hyperammonemia and that there might be a derangement in the transport of reducing equivalents across mitochondrial membranes. It has been suggested that the convulsant action of the drug is due to its effects on ionic gradients and may not be due to depletion of alpha-ketoglutarate from the citric acid cycle.

Animals↗
PubMed1985

Isolation of astrocytes, neurons, and synaptosomes of rat brain cortex: distribution of enzymes of glutamate metabolism.

A simplified method was developed for the bulk separation of neuronal perikarya and astroglial cells from adult rat brain without the involvement of density gradients. Activities of various enzymes involved in glutamate metabolism were estimated and compared with those of synaptosomes. The activities of glutamate dehydrogenase and aspartate aminotransferase were higher in synaptosomes than in neuronal perikarya or glia. Glutamine synthetase was distributed in all the three fractions while glutaminase activity was higher in astrocytes than in synaptosomes and was not detectable in neuronal perikarya. The significance of these results in relation to metabolic compartmentation was discussed.

Animals↗
PubMed1984

Suppression of the enzymes of glutamate metabolism in cortical synaptosomes in methionine sulfoximine toxicity.

Enzymes of glutamate metabolism were studied in synaptosomes prepared from normal rats and those treated with acute (300 mg/kg) and subacute (150 mg/kg) doses of the convulsant methionine sulfoximine (MSO). The activities of glutamine synthetase, glutamate dehydrogenase and aspartate aminotransferase were inhibited in the synaptosomes of drug treated animals. It is suggested that MSO would suppress the formation of glutamine and glutamate and consequently the releasable pool of glutamate, aspartate and GABA. These neurotransmitters would be depleted from the nerve endings. It is also indicated that the ammonia accumulated would affect the cerebral functioning by interfering with the maintenance of ionic gradients.

Alanine Transaminase↗