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Biomedical subjects

F Moroni

Publications and source records attributed to F Moroni.

At least 109 records · Page 6Linked to original sources
PubMed1991

Modulation of quinolinic and kynurenic acid content in the rat brain: effects of endotoxins and nicotinylalanine.

Quinolinic acid, an endogenous excitotoxin, and kynurenic acid, an antagonist of excitatory amino acid receptors, are believed to be synthesized from tryptophan after the opening of the indole ring. They were measured in the rat brain and other organs using gas chromatography-mass spectrometry or HPLC. The enzyme indoleamine 2,3-dioxygenase, capable of cleaving the indole ring of tryptophan, was induced by administering bacterial endotoxins to rats, which significantly increased the brain content of both quinolinic and kynurenic acids. Nicotinylalanine, an analogue of kynurenine, inhibited this endotoxin-induced accumulation of quinolinic acid while potentiating the accumulation of kynurenic acid. The possibility of significantly increasing brain concentrations of kynurenic acid without a concomitant increase in quinolinic acid may provide a useful approach for studying the role of these electrophysiologically active tryptophan metabolites in brain function and preventing the possible toxic actions of abnormal synthesis of quinolinic acid.

Alanine↗
PubMed1991

Influence of membrane fluidity of 5'-nucleotidase activity in isolated hepatocyte plasma membrane.

The influence of membrane microviscosity on 5'-nucleotidase activity has been investigated on liver plasma membrane preparations from rats during aging and following diet restriction. In addition the microviscosity of membranes from old rats was changed in vitro by the Active Lipids. During aging the membrane microviscosity increased progressively and in parallel the activity of 5'-nucleotidase decreased. Diet restriction was able to slow down the modification of both parameters. The experiment performed with the Active Lipids further supports that membrane microviscosity modulated the enzyme activity.

5'-Nucleotidase↗
PubMed1990

Voltage gating of Ca2(+)-activated potassium channels in human lymphocytes.

The effect of membrane potential on Ca2+ activated K+ channels was studied on human peripheral lymphocytes. Membrane potential was monitored using bisoxonol and flow cytometry. 1 mM Ca2+ in the presence of 2 microM ionomycin depolarized the control cell population, while 100 microM Ca2+ caused hyperpolarization. However 1 mM Ca2+ had a hyperpolarizing effect on previously partially depolarized cells. Potassium channel blockers did not influence the depolarization, while they inhibited the hyperpolarization. Based on the experimental evidence a voltage gating of Ca2+ activated K+ channels is suggested.

Calcium↗
PubMed1990

Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia-induced neuronal damage.

Excessive stimulation of excitatory amino acid (EAA) receptors and abnormal production of oxygen-derived free radicals have repeatedly been implicated in the series of events linking brain hypoxia or ischemia to neuronal death. We report here that in rat hippocampal slices the KCl-stimulated output of labeled D-3H aspartate or of endogenous aspartate and glutamate significantly increased under in vitro simulated hypoxic, hypoglycemic, or ischemic conditions. In particular, when the slices were incubated for 10 min at 32 degrees C under "ischemic" conditions (namely, lack of oxygen and glucose), endogenous aspartate and glutamate in the supernatant increased by 10 and 20 times, respectively. Since radical scavengers (D-mannitol), drugs reducing free radical formation (indomethacin, corticosteroid), or enzymes able to metabolize them (catalase and superoxide dismutase) significantly reduced this output, it was supposed that free radicals caused EAA release. A direct demonstration of this concept was obtained by showing a significant release of EAA after incubation of hippocampal slices with enzymes and substrates known to cause the formation of free radicals, such as xanthine plus xanthine oxidase or arachidonic acid plus prostaglandin synthase. Neither ischemia nor the enzymatic reactions leading to free radical production increased the activity of the cytoplasmic enzyme lactate dehydrogenase in the incubation medium, thus ruling out a nonspecific cellular lysis. It appears therefore that during ischemic states, brain production of reactive molecules (free radicals) causes an increased output of EAA. This may trigger a series of events which could help to explain the delayed loss of neurons after a transient ischemic period.

Amino Acids↗
PubMed1990

Antioxidant enzymes in erythrocytes from old and diet restricted old rats.

Diet restriction, prolonging the lifespan of rodents, represents an interesting model for gerontological studies. We analyzed the activity of antioxidant enzymes, Superoxide Dismutase, Catalase and Glutathione Peroxidase in erythrocytes from young, old and old food restricted Wistar rats. Diet restriction was applied feeding the animals on every-other-day schedule starting from the age of 3.5 months. The age-dependent decrease of Catalase and Glutathione Peroxidase activities was prevented by food restriction, whereas Superoxide Dismutase activity was not influenced either by aging and dietary intervention. Present results support the hypothesis that diet restriction increases the protection of cell structure against the peroxidative damage, preserving the activity of antioxidant enzymes.

Aging↗
PubMed1990

Diet restriction decreases the membrane microviscosity of cerebellar membranes of old female Wistar rats.

The microviscosity of cerebellar membranes from female Wistar rats during aging and subsequent to diet restriction has been investigated. Diet restriction was applied feeding the animals on every-other-day schedule starting from the age of 3.5 months. Undernutrition increased the lifespan of the animals and retarded the appearance of the age-dependent increase of microviscosity of cerebellar membranes.

Aging↗
PubMed1989

Systemic treatments with GM1 ganglioside reduce quinolinic acid-induced striatal lesions in the rat.

The administration of GM1 ganglioside, 30 mg/kg per day i.p., begun 3 days prior to an intrastriatal injection of the excitotoxic tryptophan metabolite quinolinic acid (QUIN) and continued for 8-16 days thereafter, significantly decreased QUIN-induced striatal damage, as evaluated by measuring the activity of the marker enzymes, choline acetyltransferase and L-glutamic acid decarboxylase. Since an increased production of QUIN has been demonstrated in Huntington's chorea patients it is possible that repeated GM1 administration could reduce the occurrence of progressive striatal neuronal loss in this neurological disorder.

Animals↗
PubMed1989

Indolpyruvic acid administration increases the brain content of kynurenic acid. Is this a new avenue to modulate excitatory amino acid receptors in vivo?

The possibility of changing the tissue content of kynurenic acid (KYNA), a tryptophan metabolite which acts as an antagonist of the excitatory amino acid receptors, was investigated by measuring its concentration in the brain, blood, liver and kidney of rats using a specific method based on ion exchange chromatography and HPLC. The administration of tryptophan (TRP) or of its keto analogue, indolpyruvic acid (IPA) (50-500 mg/kg i.p.), significantly increased, in a dose-dependent manner, the content of KYNA in various organs, including the brain. The increased brain content of KYNA after IPA administration could not be completely explained by considering that IPA may be transaminated to TRP and that the enzymes leading from TRP to KYNA are known. An alternative pathway of KYNA synthesis from IPA was therefore proposed. These findings indicate that it is possible to change the brain content of an endogenous glutamate antagonist. This could be a new avenue to modulate in vivo excitatory amino acid receptors.

Animals↗
PubMed1989

Ligand and voltage gated sodium channels may regulate electrogenic pump activity in human, mouse and rat lymphocytes.

Bretylium tosylate - a sodium channel opener - resulted in an increase of membrane potential of depolarized human, rat and mouse T and B lymphocytes. Flow cytometric membrane potential measurements with bis-oxonol revealed that the above hyperpolarizing effect was amiloride, ouabain, tetrodotoxin, azide and temperature sensitive. The effect showed an absolute dependence on the extracellular sodium but it was insensitive to the extracellular Ca2+ level. The voltage gating of the effect can be eliminated by either an increase of the extracellular potassium concentration or low doses of veratrin. The existence of a voltage and ligand gated sodium channel is suggested in the plasma membrane of all kinds of lymphocytes. The hyperpolarization is explained by an increased activity of the electrogenic sodium-potassium ATP-ase. Induced opening of such sodium channels may regulate the electrogenic pump activity and indirectly cell activation.

Amiloride↗
PubMed1989

Glycine and kynurenate modulate the glutamate receptors in the myenteric plexus and in cortical membranes.

The responses evoked by stimulation of the N-methyl-D-aspartate receptors in the guinea-pig myenteric plexus were potentiated by micromolar concentrations of glycine and were non-competitively antagonized by kynurenate (IC50: 60 microM). The effects of kynurenate were competitively prevented by glycine. Furthermore, kynurenate displaced [3H]glycine from its binding sites on rat cortical membranes (IC50: 20 microM). Kynurenate and glycine, therefore, probably act at the same site, evoking opposite effects on the function of the ion channel complex of the N-methyl-D-aspartate receptor.

2-Amino-5-phosphonovalerate↗
PubMed1989

Increase in kynurenic acid in Huntington's disease motor cortex.

Huntington's disease is a neurological disorder characterised by a progressive chorea and dementia. Recent evidence has suggested that dysfunction involving endogenous excitatory amino acids may be important in the pathogenesis of this disease. Following the recent demonstration that kynurenic acid is present in the brain, we examined the levels in various areas of brain from patients who died with Huntington's disease and from age/sex-matched controls. Blocks (100-500 mg) of cortex (Brodmann's areas 4 and 10) and caudate nucleus and globus pallidus (lateral and medial parts) were obtained from the Cambridge Brain Bank. The tissue was then processed for the extraction and analysis of kynurenic acid. Whereas no differences in the content of kynurenic acid were observed in the caudate nucleus, lateral or medial globus pallidus, or prefrontal cortex (area 10) between controls' brains and those from patients who died with Huntington's disease, there was a 94% (p less than 0.01; n = 5) increase in the kynurenic acid content in the motor cortex (area 4) from Huntington's disease brains, relative to those of controls. Some time ago we suggested that a subtle change in the relative concentrations of quinolinic and kynurenic acids might be important in the pathogenesis of neurodegeneration. It is possible that the observation of raised kynurenic acid levels supports this supposition. Further work is now in progress to determine whether the change in kynurenic acid is a primary effect or a compensatory response to an increase in excitatory activity.

Aged↗
PubMed1989

Quinoxalines interact with the glycine recognition site of NMDA receptors: studies in guinea-pig myenteric plexus and in rat cortical membranes.

1. The effects of several quinoxalines, including 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7,dinitroquinoxaline-2,3-dione (DNQX), and of two kynurenates, kynurenate (KYNA) and 7-Clkynurenate (7-Cl-KYNA), have been evaluated on the N-methyl-D-aspartate (NMDA) receptors present in the guinea-pig ileum myenteric plexus preparation and on the strychnine-insensitive [3H]-glycine binding sites of cortical membranes. 2. Quinoxalines and kynurenates antagonized in a non-competitive manner L-glutamate-induced contraction. Their IC50s were (in microM): 5 for 7-Cl-KYNA, 7.5 for 6,7-Cl-3-hydroxy-2-quinoxaline carboxylate (6,7-Cl-HQCA), 20 for DNQX, 50 for CNQX, 76 for KYNA and 125 for 3-hydroxy-2-quinoxaline carboxylate (HQCA). 3. Glycine (5-50 microM) completely reversed the antagonism displayed by both quinoxalines and kynurenates. The interaction between glycine and the tested compounds appeared to be competitive in nature. 4. Quinoxalines and kynurenates displaced, in a concentration-dependent manner, [3H]-glycine from its strychnine-insensitive binding sites present in rat cortical membranes. Their IC50s for this action were (in microM): 0.45 for 7-Cl-KYNA, 0.6 for 6,7-Cl-HQCA, 2.4 for DNQX, 3.5 for CNQX, 20 for KYNA and 40 for HQCA. 5. When the IC50s for the displacement effect of [3H]-glycine binding were plotted against the IC50s obtained in the myenteric plexus, a significant correlation was found. 6. These data show that quinoxalines and kynurenates may antagonize the responses to L-glutamate by interacting with the glycine recognition sites of the NMDA receptor ion channel complex.

Animals↗
PubMed1989

Pyrrolidone carboxylic acid in acute and chronic alcoholism. Preclinical and clinical studies.

2-Pyrrolidone-5-carboxylic acid (PCA) is a cyclic derivative of glutamic acid, physiologically present in mammalian tissues. We herein report preclinical pharmacology experiments showing that PCA releases GABA from the cerebral cortex of freely-moving guinea-pigs and displays anti-anxiety effects in a simple approach-avoidance conflict situation in the rat. In clinical pharmacology experiments, PCA significantly shortens the plasma half-life of ethanol during acute intoxication. In chronic alcoholics a treatment with PCA (2g/day per 30 days) significantly hastens the recovery to physiological values of plasma gamma-glutamyl transferase activity and of the urinary excretion of glucaric acid, which are considered suitable markers of the trend of the alcoholic disease. The evidence emerging from preclinical and clinical studies strongly suggests that, by combining central anxiolytic actions with the peripheral recovery of the antioxidant defense system in the liver, PCA should be further investigated as an interesting endogenous molecule possibly helpful in the therapy of alcoholism.

Alcoholic Intoxication↗
PubMed1989

Epirubicin high-dose therapy in advanced breast cancer: preliminary clinical data. Epirubicin as a single agent in breast cancer.

Of the new anthracycline derivatives, epirubicin is the antibiotic whose antitumor activity is comparable to that of doxorubicin while its cardiotoxicity is reduced by half. We therefore incorporated into our continuing study on anthracycline antitumor effects and toxicity a group of 22 evaluable patients, mean age 52 years, with advanced breast cancer, all of whom had previously undergone chemotherapy, radiotherapy and/or hormonal therapy. Epirubicin was administered at a dose of 120 mg/M2 every 3 weeks, for a maximum of 10 such cycles. The left ventricular ejection fraction (LVEF), determined by radionuclide ventriculography, was measured periodically in all patients. We observed 2 complete responses and 13 partial responses (CP + PR = 69%) of 61 weeks' mean duration; in 3 cases lesions remained stationary while the disease progressed in 4 patients. No patients died of acute toxicity. The main side effects were severe alopecia in 82% of the subjects and moderate degrees of nausea without vomiting in 41%. After 6 treatment cycles, 4 patients showed mild cardiotoxicity and at an epirubicin cumulative dose of 1,200 mg/M2 2 patients developed congestive heart failure (CHF). Hematological toxicity was in no case so severe as to require a reduction in the dose but only a postponement of treatment by 3 to 5 days in 9% of cycles. Without increasing hematological or cardiac toxicity, epirubicin, at a dose of 120 mg/M2, has shown itself to be a highly effective agent against advanced breast cancer.

Adult↗