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PubMed1989

Developmental changes of plasma ganglioside concentration during the neonatal period.

We investigated the developmental changes of plasma ganglioside concentration during the neonatal period. The mean plasma ganglioside concentration at birth was 8.22 +/- 3.70 nmol lipid-bound sialic acid (LBSA)/ml, significantly lower than the value in adults (12.05 +/- 1.36 nmol LBSA/ml, P less than 0.02). However, it increased rapidly early in the neonatal period and reached its maximum level at 14 days of age (16.25 +/- 6.04 nmol LBSA/ml), which was higher than that of adults (P less than 0.05); then it decreased slowly to the adult level at one month of age. The mean plasma ganglioside concentration in preterm infants (gestational age less than 37 weeks) was 6.65 +/- 3.35 nmol LBSA/ml, somewhat lower than that of fullterm infants (gestational age greater than or equal to 37 weeks, 9.90 +/- 3.39 nmol LBSA/ml, P less than 0.02) at birth. After birth, it increased much more rapidly in preterm infants and there was no significant difference between these two groups at 5 days of age. Plasma ganglioside concentration at birth increased gradually in correlation with gestational age. Our investigations show that plasma ganglioside concentration may reflect the development and maturation of the central nervous system to some degree, at least early in the neonatal period.

Adult↗
PubMed1994

Improved separation of isomeric gangliosides by anion-exchange high-performance liquid chromatography.

A new anion-exchange HPLC method for separation of gangliosides has been developed using TMAE (trimethylaminoethyl)-Fractogel as the stationary phase and a gradient system of ammonium acetate in methanol for elution. Chromatography of mouse brain gangliosides resulted in separation according not only to their degree of sialylation into mono-, di-, tri- and tetrasialogangliosides, but also in separation of positional isomers within the four elution domains, e.g. GD1a (IV3Neu5Ac,II3Neu5Ac-GgOse4Cer) and GD1b (II3(Neu5Ac)2-GgOse4Cer) of the disialoganglioside fraction. Furthermore, base-line separation of alpha 2-3 and alpha 2-6 sialylated neolacto-series gangliosides e.g. IV3Neu5Ac-nLcOse4Cer and IV6Neu5Ac-nLcOse4Cer, isolated from human granulocytes, was achieved and pure fractions of each ganglioside were obtained. Thus, the high-resolution power of the strong anion-exchanger TMAE-Fractogel allowed the isolation of pure gangliosides on a preparative scale by one-step column chromatography.

Acetates↗
PubMed1996

Postnatal development of glycosidases and gangliosides in the rat central nervous system.

The developmental profiles of sialidase, beta-galactosidase, beta-hexosaminidase and beta-glucosidase were compared to those of the gangliosides in rat brain and spinal cord. The glycosidase activities (enzyme units/g wet tissue), except beta-galactosidases, were found to be higher in brain than spinal cord, in adult rats. Among the hydrolases, beta-hexosaminidase showed a higher level of activity in both brain and spinal cord. In brain, the hydrolases, except beta-glucosidase, followed a similar developmental pattern, showing an increase from birth to 21 days, and then decreased to adult values by day 90. In the spinal cord, sialidase, beta-galactosidase, pH 3.1, and beta-hexosaminidase activities increased from birth to 21 days, reaching peak values. These activities then declined to adult values by 90 days of age. However, beta-galactosidase, pH 4.5, and beta-glucosidase activities showed a peak at day 14. Brain total ganglioside concentration (microgram N-acetylneuraminic acid/g tissue) increased slowly between birth and 7 days of age, followed by a rapid phase of increase to attain a peak value by day 21. The concentration of total gangliosides in the spinal cord is less when compared to the brain. The proportions of individual gangliosides in the central nervous system also vaired during development. The rapid phase of increase in enzyme activities between 0-7 and 14-21 days and a decrease thereafter is consistent with the turnover rate of gangliosides, which in rat brain is reported to be highest between 10 and 20 days.

Age Factors↗
PubMed1995

Gangliosides and Guillain-Barré syndrome.

Cases of Guillain-Barré syndrome (GBS) associated with parenteral use of gangliosides have been reported in several European countries. To evaluate the hypothesis of association between ganglioside exposure and occurrence of GBS, a case-control study was conducted. GBS cases discharged during 1989 from public and private hospitals in three Italian provinces were identified: 42 GBS cases and 420 controls matched on age and gender were enrolled. Data of onset of symptoms of GBS was taken from clinical records. Exposure status of subjects was ascertained through the regional computerized drug prescription monitoring system. The odds ratio of association between ganglioside use, in the 30 days prior to onset of symptoms, and GBS was 9.1 (95% confidence interval 2.8-29.4). Although there are formidable difficulties in distinguishing prodromal therapy of GBS from drug causation, the association with ganglioside therapy is strong and supportive of the hypothesis of a role of ganglioside preparations in the occurrence of GBS.

Adult↗
PubMed1996

Tumor gangliosides enhance alpha2 beta1 integrin-dependent platelet activation.

Gangliosides, sialic acid-containing glycosphingolipids, enhance platelet adhesion to collagen and consequent platelet activation. For example, gangliosides shed by neuroblastoma tumor cells (NBTG) added to a subthreshold (non-activating) concentration (1 microgram/ml) of collagen, cause platelet aggregation (59 +/- 10%) and ATP release (2.3 +/- 0.2 nmol) equivalent to that caused by 10 micrograms/ml collagen alone. Here we report further studies to characterize this effect. Platelet aggregation and ATP release were not induced by NBTG in combination with subthreshold concentrations of adenosine diphosphate, epinephrine, thrombin or arachidonic acid, suggesting that NBTG specifically influences collagen-mediated platelet activation. Maximal platelet aggregation and ATP release required extracellular magnesium and only a short (1 min) preincubation with NBTG, suggesting a collagen receptor-mediated mechanism of this ganglioside activity. Since gangliosides interact with several integrin receptors, we determined whether NBTG influences alpha 2 beta 1, a major integrin collagen receptor on platelets. Incubation of platelets with a monoclonal antibody directed against the alpha 2 chain (5E8) blocked the increase in platelet aggregation (9 +/- 3% vs. 80 +/- 2%) and ATP release ( < 0.2 vs 2.5 +/- 0.1 nmol) induced by NBTG and 1 microgram/ml collagen. Incubation with an antibody to the non-integrin collagen receptor, CD36, or with an isotype control antibody did not abrogate the effect of NBTG. Finally, NBTG and its major component, GD2, enhanced alpha 2 beta 1-mediated platelet adhesion to immobilized collagen in an antibody 5E8-inhibitable manner. These findings implicate the alpha 2 beta 1-collagen interaction as a target of the effect of tumor-derived gangliosides.

Cations, Divalent↗
PubMed2005

Different response of the knockout mice lacking b-series gangliosides against botulinum and tetanus toxins.

We assessed the response in knockout mice lacking the b-series (G(D2), G(D1b), G(T1b) and G(Q1b)) gangliosides against Clostridium botulinum (types A, B and E) and tetani toxins. We found that botulinum toxins were fully toxic, while tetanus toxin was much less toxic in the knockout mice. Combining the present results with our previous finding that tetanus toxin and botulinum types A and B toxins showed essentially no toxic activity in the knockout mice lacking both the a-series and b-series gangliosides (complex gangliosides), we concluded that the b-series gangliosides is the major essential substance for tetanus toxin, while b-series gangliosides may be not the essential substance for botulinum toxins, at the initial step during the intoxication process in mouse.

Animals↗
PubMed2004

Gangliosides of organ-confined versus metastatic androgen-receptor-negative prostate cancer.

Prior development of a unique androgen-receptor (AR)-negative cell line (HH870) from organ-confined (T2b) human prostate cancer (CaP) enabled comparison of the gangliosides associated with normal and neoplastic prostate epithelial cells, organ-confined versus metastatic (DU 145, PC-3), and AR-negative versus AR-positive CaP cell lines. Resorcinol-HCl and specific monoclonal antibodies were used to characterize gangliosides on 2D-chromatograms, and to visualize them on the cell surface with confocal-fluorescence microscopy. AR-negative cells expressed GM1b, GM2, GD2, GD1a, and GM3. GM1a, GD1b, and GT1b were undetectable. GM1b and GD1a were more prominent in AR-negative than in AR-positive cells. PC-3 and HH870 cells were unique in the expression of O-acetylGD2 (O-AcGD2) and two alpha2,3-sialidase-resistant, alkali-susceptible GMR17-reactive gangliosides. Expression of GD1a, GM1b, doublets of GD3, GD2, and O-AcGD2, and the presence of an additional alkali-labile-14.G2a-reactive ganglioside, two alkali-susceptible, and three alkali-resistant GMR17-reactive gangliosides makes HH870 a potential component of a polyvalent-vaccine for active-specific immunotherapy of CaP.

Animals↗
PubMed2006

Anti-ganglioside antibodies in coeliac disease with neurological disorders.

BACKGROUND: Anti-ganglioside antibodies have been described in sera of coeliac patients with peripheral neuropathy and cerebellar ataxia. AIMS: To investigate the correlation between anti-ganglioside antibodies and neurological involvement in coeliac disease before and after gluten-free diet. PATIENTS AND METHODS: Twenty-two untreated coeliac patients with neurological dysfunction and 30 untreated coeliacs without neurological dysfunction, 20 patients with neurological disorders, 50 autoimmune disease and 20 blood donors were tested for anti-GM1, anti-GD1b and anti-GQ1b IgG and IgM antibodies by enzyme-linked immunosorbent assay. RESULTS: IgG antibodies to at least one of the three antigens tested were positive in 64% of coeliac patients with neurological symptoms compared to 30% of coeliacs without neurological dysfunction (P=0.02), 50% of patients with neurological disorders (P=ns), 20% with autoimmune diseases (P=0.003) and none of blood donors (P=0.0001). A strict gluten-free diet determined anti-ganglioside antibody disappearance in about half of coeliacs. CONCLUSIONS: A significant correlation between anti-ganglioside antibodies and neurological disorders in patients with an underlying coeliac disease has been found. Anti-ganglioside antibodies may represent a new immunological marker to identify neurological impairment in patients with coeliac disease.

Adult↗
PubMed2005

Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PNS: neuropathology and behavioral deficits in single- and double-null mice.

Complementary interacting molecules on myelin and axons are required for long-term axon-myelin stability. Their disruption results in axon degeneration, contributing to the pathogenesis of demyelinating diseases. Myelin-associated glycoprotein (MAG), a minor constituent of central and peripheral nervous system myelin, is a member of the Siglec family of sialic acid-binding lectins and binds to gangliosides GD1a and GT1b, prominent molecules on the axon surface. Mice lacking the ganglioside biosynthetic gene Galgt1 fail to express complex gangliosides, including GD1a and GT1b. In the current studies, CNS and PNS histopathology and behavior of Mag-null, Galgt1-null, and double-null mice were compared on the same mouse strain background. When back-crossed to >99% C57BL/6 strain purity, Mag-null mice demonstrated marked CNS, as well as PNS, axon degeneration, in contrast to prior findings using mice of mixed strain background. On the same background, Mag- and Galgt1-null mice exhibited quantitatively and qualitatively similar CNS and PNS axon degeneration and nearly identical decreases in axon diameter and neurofilament spacing. Double-null mice had qualitatively similar changes. Consistent with these findings, Mag- and Galgt1-null mice had similar motor behavioral deficits, with double-null mice only modestly more impaired. Despite their motor deficits, Mag- and Galgt1-null mice demonstrated hyperactivity, with spontaneous locomotor activity significantly above that of wild type mice. These data demonstrate that MAG and complex gangliosides contribute to axon stability in both the CNS and PNS. Similar neuropathological and behavioral deficits in Galgt1-, Mag-, and double-null mice support the hypothesis that MAG binding to gangliosides contributes to long-term axon-myelin stability.

Animals↗
PubMed1997

Gangliosides involved in activation of rat T lineage cells.

Gangliosides have long been known to be involved in T-cell activation. In our previous studies, a unique GMlb-derived ganglioside, GD1c(NeuGc,NeuGc), was shown to be the predominant ganglioside in rat thymocytes and T-cells. Upon the activation of the thymocytes, the amount of GD1c(NeuGc,NeuGc) increases remarkably, and additionally a novel species of GD1b, GD1b(NeuGc,NeuGc), appears as the other major ganglioside (Nohara, et al. (1993) J. Biol. Chem. 268, 24997-25000). In the present study, monoclonal antibodies (MAbs) against these two gangliosides have been generated. The MAb AC1 established by immunizing mice with purified GD1c(NeuGc,NeuGc) reacted strongly with GD1c(NeuGc,NeuGc) and weakly with GD1b(NeuGc,NeuGc) by enzyme-linked immunosorbent assay (ELISA). The other MAb AB1 obtained by immunization with GD1b(NeuGc,NeuGc) showed a strong binding activity to GD1b(NeuGc,NeuGc) and no reactivity to GDlc(NeuGc,NeuGc) by ELISA. Flow cytometry analyses using these MAbs have revealed that an AC1-positive subset exists in a portion of resting CD4+CD8- thymocytes and CD4+ splenic T-cells. When the thymocytes were activated with 12-O-tetradecanoylpholbol-13-acetate (TPA) and calcium ionophore A23187, the proportion of AC1+ cells increased remarkably and were detected not only in CD4+ cells but also in CD8+ cells. An increase in the proportion of AC1+ cells was also seen in activated T-cells. In contrast, AB1-positive cells were only detected in activated thymocytes, not in resting thymocytes, or resting or activated T-cells. These results implicate GD1c(NeuGc,NeuGc) in the activation of thymocytes as well as T-cells, whereas GD1b(NeuGc,NeuGc) appears to be specifically related to the activation of thymocytes.

Animals↗
PubMed1984

Ganglioside composition of substrate-adhesion sites of normal and virally-transformed Balb/c 3T3 cells.

The ganglioside composition of the so-called substrate-attached material (SAM), which remains tightly bound to the tissue culture dish after cells are detached by chelating agents, was compared with the ganglioside composition of released cell bodies in the cultures of normal and various virally-transformed Balb/c 3T3 cells. Regardless of whether the cells were untransformed or transformed, the SAM of their cultures shows a ganglioside structure characterized by a prevalence of the higher homologs, mainly GD1a, over the simpler gangliosides, even when the level of higher homologs was reduced in the cell bodies of transformed cells. This result cannot be ascribed to the presence of plasmamembranes in the SAM as shown by ganglioside analysis of the plasmamembranes of some of the cells under study. Only in a highly metastatic transformed cell line did the SAM contain the same low GD1a level as found in the cell bodies.

Animals↗
PubMed1998

Naturally occurring ganglioside lactones in Minke whale brain.

Ganglioside lactones in Minke whale brain were analysed. In order to exclude the possibility of the artificial lactonization of gangliosides during the analytical procedures, lactone species were separated from their parent gangliosides at an early stage by DEAE-Sephadex A-25 column chromatography using a stepwise elution. Applying the improved method, GM41 lactones were found in grey and white matters of cerebrum and cerebellum, while GD3 monolactone was found only in cerebellar gray matter. The concentration of each ganglioside lactone was one thousandth of the parent ganglioside.

Animals↗
PubMed1999

Nerve growth factor, ganglioside and vitamin E reverse glutamate cytotoxicity in hippocampal cells.

The present work showed that glutamate decreased hippocampal cell viability in a dose-dependent manner. While no significant effect was observed after cell exposure to 0.1 mM glutamate, cell incubation for 0.5 h caused a progressive decrease of cell viability, which at 5 mM concentration reached 68% as compared to controls. No further effect was observed in the presence of 10 mM glutamate. While nerve growth factor (NGF) at the dose of 0.5 ng/ml presented no effect, it significantly reduced glutamate cytotoxicity at a higher dose (1 ng/ml) increasing the cell viability to 66%. Similarly, cell viabilities in the presence of the ganglioside GM, (5 and 10 ng/ml) after glutamate exposure were 19 and 73%, respectively. A dose-response relationship was observed after cell incubation with vitamin E (0.5 and 1 mM) which resulted in cell viability of the order of 34 and 70%, respectively. Surprisingly, a potentiation of the effect was observed after the association of NGF (0.5 ng/ml) plus ganglioside GM1 (5 ng/ml) or vitamin E (0.5 mM) plus ganglioside GM1 (5 ng/ml), after pre-incubation with glutamate. In these conditions, significantly higher viabilities were demonstrated (66 and 71% for the two associations, respectively) as compared to each one of the compounds alone (NGF 0.5 ng/ml--29.5%; ganglioside GM1 5 ng/ml--19.4%). However, no potentiation was seen after the association of NGF plus vitamin E on glutamate pre-exposed cells. These results showed a cytoprotective effect of ganglioside GM1, NGF and vitamin E on the glutamate-induced cytotoxicity in rat hippocampal cells.

Animals↗
PubMed1997

The interaction between Alzheimer amyloid beta(1-40) peptide and ganglioside GM1-containing membranes.

The interaction between Alzheimer amyloid peptide A beta(1-40) and membrane lipids was studied by circular dichroism spectroscopy under the conditions of physiologically relevant ionic strength and neutral pH. The peptide binds to the membranes containing ganglioside GM1 and upon binding undergoes a conformational transition from random coil to an ordered structure rich in beta-sheet. This interaction appears to be ganglioside-specific as no changes in A beta(1-40) conformation were found in the presence of various phospholipids or sphingomyelin. The isolated oligosaccharide moiety of the ganglioside was ineffective in inducing alterations in the secondary structure of A beta(1-40). No interaction was observed between ganglioside GM1 and the N-terminal peptide fragment A beta(1-28). Binding to the ganglioside is likely to modulate the neurotoxic and/or amyloidogenic properties of A beta(1-40).

Amyloid beta-Peptides↗
PubMed1987

New solvent system for high-performance thin-layer chromatography and high-performance liquid chromatography of gangliosides.

New solvent systems consisting of acetonitrile, isopropanol and aqueous 50 mM potassium chloride or 2.5 M ammonium hydroxide were developed for the separation of gangliosides by high-performance thin-layer chromatography. These solvent systems seem to be superior for the resolution of polysialogangliosides such as tetra-, penta- and hexasialo species, as compared to chloroform-methanol-aqueous salt systems. The order of mobility of gangliosides in the ammoniacal solvent system is GD3 greater than GD1a greater than GM1 greater than GT1b greater than GD1b as compared with GM1 greater than GD3, GD1a greater than GD1b greater than GT1b in the neutral septem. A combination of these two solvent systems provides excellent two-dimensional separations of complex ganglioside mixtures. The neutral solvent system, acetonitrile-isopropanol-aqueous 50 mM potassium chloride, can be used for the separation of underivatized gangliosides by high-performance liquid chromatography on an Aquasil SS silica gel column. Ganglioside elution can be monitored at 208 nm because of the good UV-transparency of the effluent.

Chromatography, High Pressure Liquid↗
PubMed1997

Analysis of gangliosides by capillary zone electrophoresis and capillary zone electrophoresis-electrospray mass spectrometry.

Gangliosides, sialic acid(s)-containing glycosphingolipids, were separated by capillary zone electrophoresis and detected with either UV or electrospray mass spectrometry. Several electrolyte system were evaluated for the separation of underivatized gangliosides. The best result was obtained by using 50 mM borate and 50 mM phosphate buffer containing 20 mM alpha-cyclodextrin at pH 9.9. The four major ganglioside forms (GM1, GD1a, GD1b, GT1b) were successfully separated, and, moreover, each ganglioside yielded two peaks, splitting by the difference in chain length of the ceramide moiety. The resolution obtained in CE-UV could not be reproduced in CE-MS because of the incompatibility of the borate/phosphate buffer to ESI-MS. With the use of more volatile buffers, such as ammonium acetate or 2-[N-cyclohexylamino]-ethanesulfonic acid, baseline resolution was obtained for gangliosides having different number of sugars, but the two disialoganglioside isomers, GD1a and GD1b, were coeluted.

Animals↗
PubMed1998

Addition of gangliosides to an adapted milk formula modifies levels of fecal Escherichia coli in preterm newborn infants.

Because some gangliosides bind bacteria, we tested the influence of supplementating an adapted milk formula with gangliosides, at a total concentration of 1.43 mg/100 kcal, on the fecal microflora of preterm infants. At all sampling times, feces from infants fed with ganglioside-supplemented formula had significantly lower relative content of Escherichia coli than feces from infants fed with control milk formula: the difference was especially significant at age 7 days postnatal < .001). At age 30 days postnatal, fecal bifidobacterial counts were higher in infants fed with ganglioside-supplemented formula (P < .05). We conclude that gangliosides at concentrations present in human milk significantly modify the fecal flora.

Escherichia coli↗
PubMed1994

Detection of glioma-associated gangliosides GM2, GD2, GD3, 3'-isoLM1 3',6'-isoLD1 in central nervous system tumors in vitro and in vivo using epitope-defined monoclonal antibodies.

In this study, MAbs to the 'conventional' gangliosides expressed by human gliomas were generated and used to detect ganglioside species previously unisolated or defined in normal adult CNS tissue. Despite the marked phenotypic and genotypic heterogeneity shown by glioma cell lines (Bigner et al., 1981), the ganglioside phenotype of these cell lines is remarkably consistent qualitatively, if not quantitatively, in the ganglioside species expressed (Table V). The majority of cell lines and tumor samples express GM2, GD2 and GD3; this does not provide a diagnostic advantage (Vick et al., 1992). Nevertheless, as the relative amounts of these gangliosides in tumor as compared with normal adult CNS tissue is considerable, such reagents might be considered in compartmental immunotherapeutic approaches. Since GD2 and GD3 have been determined to mediate tumoricidal activity with human effector cells via specific antiganglioside epitope MAbs (Thurin et al., 1987; Kushner and Cheung, 1991; Barker et al., 1991; Reisfeld, 1993), cell-mediated approaches, as well as targeted immunoglobulin therapies, are also possible. The prospect of a more targeted approach with little or no effect on normal CNS tissue is now possible via the 'oncofetal' epitopes characteristic of 3'-isoLM1 and 3',6'-isoLD1. Several factors recommend the use of these moieties for compartmental immunotherapy; the inability to detect them within the adult CNS; the relatively high frequency of expression of 3'-isoLM1 and 3',6'-isoLD1, especially in human tumor samples (50-100%, depending upon the series and assay); and the existence of specific MAbs reactive with these epitopes. Current technology is being applied to these MAbs to transfer the specific recognition capacity of existing murine MAbs into various human framework structures of any desired immunoglobulin class, and thereby, biologic function. The variety of effector functions, the stability in affinity, labeling capacity, and the exquisite sensitivity of these MAbs for these glioma-distinctive epitopes is an exciting and promising approach for immunotherapy of human CNS tumors.

Antibodies, Monoclonal↗