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Biomedical subjects

M Kozma

Publications and source records attributed to M Kozma.

At least 19 recordsLinked to original sources
PubMed2000

Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain alpha-keto acid dehydrogenase that can result in neurodegenerative sequelae in human infants. In the present study, increased concentrations of MSUD metabolites, in particular alpha-keto isocaproic acid, specifically induced apoptosis in glial and neuronal cells in culture. Apoptosis was associated with a reduction in cell respiration but without impairment of respiratory chain function, without early changes in mitochondrial membrane potential and without cytochrome c release into the cytosol. Significantly, alpha-keto isocaproic acid also triggered neuronal apoptosis in vivo after intracerebral injection into the developing rat brain. These findings suggest that MSUD neurodegeneration may result, at least in part, from an accumulation of branched chain amino acids and their alpha-keto acid derivatives that trigger apoptosis through a cytochrome c-independent pathway.

Amino Acids, Branched-Chain↗
PubMed2000

Primary human fibroblasts from a maple syrup urine disease patient undergo apoptosis following exposure to physiological concentrations of branched chain amino acids.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a deficiency in branched chain alpha-ketoacid dehydrogenase. We have recently found that MSUD neurodegeneration may result, at least in part, from apoptosis triggered by branched chain amino acids and their alpha-ketoacid derivatives. In the present study, we investigated the sensitivity of MSUD fibroblasts to defined mixtures of MSUD metabolites. Defined combinations of MSUD metabolites, at levels comparable to those in MSUD patients, triggered cell death in skin fibroblasts from a MSUD patient, while control fibroblasts were resistant. The mechanism of cell death was confirmed as apoptosis by in situ end labeling.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2000

Fas/CD95/APO-1 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischemic injury to the developing rat brain.

Fas/CD95/Apo-1 is a cell surface receptor that transduces apoptotic death signals following activation and has been implicated in triggering apoptosis in infected or damaged cells in disease states. Apoptosis is a major mechanism of neuronal loss following hypoxic-ischemic injury to the developing brain, although the role of Fas in this process has not been studied in detail. In the present study, we have investigated the expression and function of Fas in neuronal cells in vitro and in vivo. Fas was found to be expressed in the 14 day old rat brain, with strongest expression in the cortex, hippocampus and cerebellum. Cross-linking of Fas induced neuronal apoptosis both in neuronal PC12 cells in culture and following intracerebral injection in vivo, indicating that neuronal Fas was functional as a death receptor. This death was shown to be caspase dependent in primary neuronal cultures and was blocked by the selective caspase 8 inhibitor IETD. Finally, cerebral hypoxia-ischemia resulted in a strong lateralised upregulation of Fas in the hippocampus, that peaked six to twelve hours after the insult and was greater on the side of injury. These results suggest that Fas may be involved in neuronal apoptosis following hypoxic-ischemic injury to the developing brain.

Animals↗
PubMed1999

Poly(ADP ribose) polymerase cleavage precedes neuronal death in the hippocampus and cerebellum following injury to the developing rat forebrain.

Transient unilateral forebrain hypoxia-ischaemia (HI) in 14-day-old rats produces infarction and delayed neuronal death in the frontal cortex. Cell death can also be observed in regions distant from the primary injury, a phenomenon known as diaschisis. While apoptosis is involved in selective neuronal death, its role in infarction and diaschisis remains poorly understood. Here, we have investigated the proteolytic cleavage of poly(ADP ribose) polymerase (PARP) and the occurrence of apoptosis in the hippocampus and the cerebellum following either HI or traumatic brain injury. We demonstrate that: (i) in vitro, PARP is cleaved during apoptosis but not necrosis in cultured neuronal (N1E) cells and Swiss 3T3 fibroblasts; (ii) following HI, apoptotic cells can be detected by 4 h after injury in the hippocampus; (iii) in the ipsilateral hippocampus the appearance of cells with apoptotic morphology is preceded by a dramatic increase in PARP cleavage in the same region, starting immediately following HI and persisting for 24 h; (iv) HI also induces apoptosis in the cerebellum and, as in the hippocampus, the appearance of cells with apoptotic morphology is preceded by PARP cleavage that is greater on the side ipsilateral to forebrain injury; and (v) similarly, traumatic brain injury to the forebrain leads to PARP cleavage and apoptosis in the cerebellum. We conclude that HI injury or traumatic injury to the developing rat forebrain leads to PARP cleavage in directly affected areas and in sites distant from the primary injury that precedes the appearance of cells with apoptotic morphology. Our results are consistent with a role for apoptotic cell death in infarction and in diaschisis resulting from forebrain injury to the developing brain.

3T3 Cells↗
PubMed1989

[Results of 3-year study of toothbrushing with a fluoride amine gel].

265 6-year-old children were investigated over a period of 3 years. In the test group, 6 toothbrushing exercises and 25-30 controlled applications of Elmex Gelèe were carried out yearly. The effect was analyzed by oral hygiene, caries frequency, caries intensity, and caries increase. The improvement of the oral hygiene index according to Silness-Löe was 30% and can be characterized as highly statistically significant (p less than 0.001). The inhibition of caries increase related to the surface (delta DMF-S) was 53% in the case of caries with substance loss and was also highly significant.

Amines↗
PubMed1988

Vasoactive intestinal peptide synergistically stimulates DNA synthesis in mouse 3T3 cells: role of cAMP, Ca2+, and protein kinase C.

Vasoactive intestinal peptide synergistically stimulated initiation of DNA synthesis in Swiss 3T3 cells. The peptide stimulated [3H]thymidine incorporation in the presence of insulin and either forskolin or an inhibitor of cAMP phosphodiesterase in a concentration-dependent manner. Half-maximal effect was obtained at 1 nM. At mitogenic concentrations, VIP stimulated a marked accumulation (eightfold) of cAMP. In contrast to other growth-promoting neuropeptides, VIP did not induce an increase in cytosolic free Ca2+ or an activation of protein kinase C. We conclude that neuropeptides can modulate long-term cell proliferation through multiple signaling pathways.

Animals↗
PubMed1986

Studies on the pharmacokinetics and metabolism of N(4)-carbamoyl-1,3,4,5-dihydro-diazepam (Uxepam(R)) in rats, dogs and man.

The pharmacokinetics and metabolism of Uxepam(R), a new minor tranquillizer, have been investigated in rats [2], dogs and man. For the experiments in rats [2] separation of metabolites of 2-(14)C-uxepam was achieved by thin-layer chromatography. In the experiments on dogs and man, Extrelut microcolumns were used for preseparation. Recovery was 95% +/- 12.77 (S.D.) determined by radioactive tracer experiments. The compounds were separated and determined by reversed-phase HPLC with UV detection at 240 nm. The limit of detection for uxepam was 10 ng ml(-1). The metabolises were identified by mass spectrometry. The main metabolites in the rat were desmethyl-uxepam, 5-hydroxy-phenyl-desmethyl-uxepam and diazepam. Desmethyl-carbamoyl-dihydro-diazepam, diazepam and desmethyl-diazepam were found in human plasma. In dogs only one metabolite, desmethyl-uxepam, was detected in plasma. Enterohepatic recycling was observed in dogs and in humans.

Journal Article↗
PubMed1982

Determination of apovincaminic acid in biological samples by high-performance liquid chromatography.

A method is described for measuring the concentrations of apovincaminic acid and vincaminic acid (internal standard) in blood plasma and urine by high-performance liquid chromatography using ion pair extraction. The main metabolite of vinpocetine, apovincaminic acid, and vincaminic acid were extracted from 1 ml of plasma and urine into chloroform as an ion pair using tetrabutylammonium hydroxide as counter ion. Analysis was carried out on a reversed-phase column of RP-8 with acetonitrile-0.0075 M phosphate buffer (28:72) at pH 3.5 as mobile phase. The eluted derivatives were detected by UV absorption at 254 nm. The sensitivity of the method is 20 ng/ml for AVA in plasma and urine samples. The relative recovery of these compounds added to plasma was about 50%.

Chromatography, High Pressure Liquid↗
PubMed1982

Zinc deficiency-induced trace element concentration and localization changes in the central nervous system of albino rat during postnatal development. II. Atomic absorption spectrophotometric examinations.

The changes in the zinc and copper concentrations in the central nervous system (spinal cord, cerebellum, cerebrum, hippocampus, corpus striatum) of albino rat were studied by atomic absorption spectrophotometry in a state of zinc deficiency induced experimentally during the first 30 days of postnatal ontogenesis. It was found that in these structures the zinc deficiency is able to influence the changes and tendencies in the trace element content essentially only in an area undergoing intensive development in the given period, or which is sensitive to unsatisfactory dietary influences. The results lead to the assumption that the state of zinc deficiency is accompanied by a change in the distribution of the trace element content within the cells.

Animals↗
PubMed1981

Histochemical detection of zinc and copper in various neurons of the central nervous system.

Trace elements (Zn2+, Cu2+, Fe2+) were localized with Timm's sulphide silver method in the neurons (pyramidal cells, Purkinje's cells, motoneurons) and in the axon terminals of various regions cortex, hippocampus, nucleus ruber, cerebellum, medulla spinalis) of the central nervous system. After treatment of the same tissues with 15% trichloroacetic acid, a considerable proportion of the coarse granular staining disappeared from certain neurons (Purkinje's cells, ncl. ruber cells, motoneurons) and axon terminals (hippocampus mossy fibres), while in other cells (cortex pyramidal cells) and axon terminals it remained. The results suggest that the decrease in the staining is a consequence of the loss of Zn2+ and Fe2+ from the neuronal perikaryon or axon terminal. The histochemical results are supported by quantitative atomic absorption measurements.

Animals↗